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Pharmacology of Resistant Hypertension

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Pharmacology of Resistant Hypertension 7/25/2013 47th Annual Meeting ҉ August 2-4, 2013 ҉ Orlando, FL Presenter Disclosure Information Financial Disclosure: I do not have a vested interest in or affiliation with any Pharmacology of corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an organization whose Resistant Hypertension philosophy could potentially bias my presentation. Other Disclosures: I have participated in the development of the “PRA and David Parra, Pharm.D., FCCP, BCPS HTN” app for the iPhone and Android smartphones. The app guides the user Clinical Pharmacy Specialist, Cardiology in the use of plasma renin activity to guide anti‐hypertensive therapy. I West Palm Beach VAMC received no compensation for its development or for its use which is available for download free of charge. Clinical Associate Professor Department of Experimental and Clinical Pharmacology College of Pharmacy, University of Minnesota The views expressed in this presentation reflect those of the author, and not necessarily those of the Department of Veterans Affairs. Objectives Consequences of Uncontrolled Hypertension •Describe the general approach to the drug management of resistant hypertension •Recognize commonly prescribed medications that may impede blood pressure control •Compare and contrast the pharmacokinetics/ancillary properties of antihypertensive agents to select the most appropriate agent when presented with a patient case • Apply the concept of plasma renin activity to help guide treatment decisions with antihypertensive agents Messerli F. N Engl J Med 1995;332:1038-1039 Prevalence, Treatment, and Headlines of the St. Louis Post-Dispatch, April 13, 1945 Control of Hypertension 1999–2002 & 2005–2008 Percent of U.S. Adults Percent ofU.S. Centers for Disease Control and Prevention. Vital signs: Prevalence, treatment, and control of hypertension—United States, 1999-2002 and 2005-2008. MMWR Morb Reprinted with permission Mortal Wkly Rep 2011; 60:1-6. 1 7/25/2013 Resistant Hypertension Prevalence of Resistant Hypertension • Failure to achieve goal blood pressure in adherent •Observational estimates patients despite 3 antihypertensive agents from •NHANES 2005‐2008 – 20.7% different classes •Tertiary Hypertension Centers –11‐38% • Ideally one agent should be a diuretic •ASH (Carolinas, Florida, Georgia Chapter) 2007 – 16.2% •All should be at optimal doses • Clinical trial estimates • Includes patients whose blood pressure is • ALLHAT, ASCOT, ACCOMPLISH, LIFE, CONVINCE, and INVEST suggest up to 35% controlled but require 4 or more medications • Difficult to establish Calhoun DA et al. Resistant hypertension: Diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension. BMJ 2012;345:e7473. 2008;51:1403-19. Curr Opin Cardiol. 2012;27:386-91. Early (1930) Antihypertensive Therapies Animasa Mistletoe Benzyl benzoate “Natheim” bath Benzyl succinate Nitroscleran Calcium diuretin Potassium sulphocyanate Calcium Salts and low protein diet Radiation of the skull Corpus luteum Radium water Desecin Subtonin Diathermy Sodium sulphocyanate Irradiation of suprarenal region Theominal Liver extract Thyroid and potassium Lumbar sympathectomy permanganate Luminal Watermelon extract Hypertension. 2011;57:1045-46. Curr Opin Cardiol. 2012;27:386-91 Ayman. JAMA 1930:95:246 Current Oral Antihypertensive Agents •bumetanide • nebivolol • lisinopril • isradipine •ethacrynic acid • bisoprolol • perindopril • nicardipine •furosemide • pindolol • azilsartan • nifedipine •torsemide The question remains: • hydrochlorothiazide • timolol • candesartan • nimodipine • chlorothiazide • bucindolol • eprosartan • nitrendipine • indapamide • carvedilol • irbesartan • diltiazem What approaches can be used to • chlorthalidone • labetalol • losartan • verapamil • metolazone •captopril • olmesartan • clonidine improve control, particularly in • amiloride •triamterene • enalapril • telmisartan • guanabenz • eplerenone • fosinopril • valsartan • guanfacine patients with resistant • spironolactone •moexipril • doxazosin • methyldopa • propranolol • quinapril • terazosin • minoxidil hypertension? •atenolol •ramipril • prazosin • hydralazine • acebutolol • trandolapril • aliskiren • guanethidine •metoprolol • benazepril • amlodipine • reserpine • nadolol • felodipine 2 7/25/2013 Patient Characteristics Associated with Resistant Hypertension Lifestyle Factors Contributing to Resistant Hypertension •High baseline blood pressure •Older age • Obesity or overweight •Obesity • Excessive dietary salt ingestion •High salt diet •Chronic kidney disease •Physical inactivity •Diabetes •Left ventricular hypertrophy • Ingestion of low‐fiber, high‐fat diet •African American race •Female gender •Heavy alcohol ingestion • Residence in Southeastern United States Hypertension. 2008;51:1403-1419 Hypertension. 2008;51:1403-1419 General Approach to Resistant Primary Cause of Resistant Hypertension Hypertension Cause of resistance found in 133/141 – 94% (83/91 – 91%) cases Office Unknown • Confirm treatment resistance resistance 6% 6% Nonadherence Psychological 16% • Exclude pseudoresistance (24hr measurements) causes 9% • Address contributing lifestyle factors Secondary HTN • Discontinue or minimize interfering substances 5% • Screen for secondary causes of hypertension Interfering substances • Document target organ damage 1% Drug-related causes • Confirm appropriate treatment 58% Hypertension. 2008;51:1403-1419 Garg JP, et al. Am J Hypertens 2005;18:619-26 Substances Impeding Blood Pressure Control: Mechanisms of Interference •Sodium and water retention • Activation of the sympathetic nervous system • Activation of the renin–angiotensin system Volpe M, Tocci G. Challenging Hypertension: How to Diagnose and Treat Resistant Garg JP, et al. Am J Hypertens 2005;18:619-626 Hypertension in Daily Clinical Practice Expert Rev Cardiovasc Ther. 2010;8(6):811-820. 3 7/25/2013 Commonly Recognized Substances Less‐Commonly Recognized Substances Impeding Impeding Blood Pressure Control Blood Pressure Control • Non-steroidal anti-inflammatory agents •Neurologic and psychiatric agents • Sympathomimetic agents • Tricyclic antidepressants, SNRIs (e.g. venlafaxine), • decongestants, diet pills, cocaine •Modafanil • methylphenidate, amphetamine salts •Herbal compounds • Alcohol •Ma huang (ephedra), bitter orange, blue cohosh, • Corticosteroids ginseng, guarana • Cyclosporine, tacrolimus •Vascular endothelial growth factor inhibitors • Erythropoietin stimulating agents • Bevacizumab • Estrogens (including oral contraceptives) •Sorafenib • Migraine medications • Sunitinib • Natural licorice VEGF Inhibitors and Hypertension: Potential Mechanisms Treatment of Resistant Hypertension: 2008 AHA Statement •Non‐Pharmacologic Recommendations • Pharmacologic Recommendations • Withdrawal or down titration of interfering substances •Use of a long‐acting thiazide diuretic (i.e. chlorthalidone) • Combine agents with different mechanisms of action •Triple regimen of ACE inhibitor or ARB, calcium channel blocker, and thiazide diuretic Granger, J. P. Hypertension 2009;54:465-467 Hypertension. 2008;51:1403-1419 Diuretics and Their Treatment of Resistant Hypertension: 2008 Primary Sites of Action AHA Statement • Addition of mineralocorticoid receptor antagonist •Use of loop diuretic in patients with CKD (creatinine clearance <30 ml/min) •If blood pressure controlled consider adjustment of the treatment regimen to maintain control but with use of fewer medications and/or with use of a regimen that minimizes adverse effects • Need for additional knowledge (research) to identify and effectively treat these patients Hypertension. 2008;51:1403-1419 4 7/25/2013 Thiazide Diuretics Common Thiazide Diuretics Effective when CrCl > 30ml/min (exception metolazone) • Excellent in combination with other agents t ½ Relative Elimination Anti-hypertensive dosing Absorption (hr) potency R=Renal H=Hepatic (typical) •Have been considered generally B=Biliary U=unknown interchangeable 65% R Chlorthalidone ~65% ~47 1 12.5-25mg po once daily •Same pharmacologic effects 10% B, 25% U • Appropriate dose adjustment required HCTZ ~70% ~2.5 1 R 12.5-50mg po once daily Indapamide • Equivalent clinical efficacy? ~93% ~14 20 >95% H 1.25-5 mg po once daily •Different pharmacokinetics and subsequent 80% R, 2.5-5mg po once daily Metolazone ~65% 4-5 10 pharmacodynamics 10%H, 10%B For Mykrox®: 0.5-1mg po QD * Dose dependent, HCTZ= Hydrochlorothiazide Hardman JG, Limbird LE, Gilman AG. (Eds.). (2001) Goodman & Gilman's the pharmacological basis of therapeutics. (10th ed.). New York: McGraw-Hill. Lacy CF, Armstrong LL, Goldman MP, Lane LL (Eds.). (2005) Lexi-Comp’s Drug Information Handbook (13th ed.). Hudson Ohio: Lexi-Comp Antihypertensive Effects of Hydrochlorothiazide Are All Thiazides Equal? versus Chlorthalidone on Blood Pressure Chlorthalidone versus hydrochlorothiazide •Half‐life, duration of action •Less braking phenomenon? • ALLHAT, MRFIT versus ANBP2 •24‐hour ambulatory blood pressure comparison (Ernst et al. Hypertension. 2006;47:352‐358.) Khosla N, Chua DY, Elliott, WJ, Bakris G. The Journal of Clinical Hypertension 2005;7(6): 354-346. Antihypertensive Effects of Hydrochlorothiazide Antihypertensive Efficacy of versus Chlorthalidone on Blood Pressure HCTZ as Evaluated by ABPM Mean change from week 0 to week 8 in average hourly ambulatory systolic BP. p<0.001 for HCTZ 12.5-25mg vs. other antihypertensives
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