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Newer Antihypertensive Drugs BushraAbdul Hadi Philadelphia University.

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Presentation on theme: "Newer Antihypertensive Drugs BushraAbdul Hadi Philadelphia University."— Presentation transcript:

1 Newer Antihypertensive Drugs BushraAbdul Hadi Philadelphia University

2 Peripheral vascular disease  Morbidity  Disability Renal disease CAD CHF LVH Stroke Hypertension National High Blood Pressure Education Program Working Group. Arch Intern Med. 1993;153: Hypertension: A Significant CV and Renal Disease Risk Factor

3 “Older generation drugs used to bring down the B.P. fairly well at reasonable cost.” Then, Why do we need new drugs ? Observational and limited controlled trials then showed marginal benefits of BP lowering for CVAs and IHD Unfriendly dosing schedule Unpleasant side effects

4 Vasculopathy continuum Risk Factors Endothelial Dysfunction CAD CHF CVA PAD CKD HTN Metabolic syndrome

5 Hypertension Na + Handling Sympathetic N system RAAS Genetics Environment Psycho-social

6 HTN : Old and New Diuretics Reserpine Guanethidine Alpha Methyl Dopa ACE Inhibitors Angiotensin Receptor Blockers Beta Blockers Central Alpha Agon. Calcium Channel Blockers Diuretics Direct Vasodilators Aldosterone Anta. NEP Blockers

7  Heart –Myocardial hypertrophy –Interstitial fibrosis  Coronary Arteries –Endothelial dysfunction with decreased release of nitric oxide –Coronary constriction via release of norepinephrine –Formation of oxygen-derived free radicals via NADH (nicotinamide adenine dinucleotide) oxidase –Promotion of inflammatory response and plaque instability –Promotion of low-density lipoprotein cholesterol uptake Adapted from Opie and Gersh. Drugs for the Heart, Potential Pathogenic Properties of Angiotensin II

8  Kidneys –Increased intraglomerular pressure –Increased protein leak –Glomerular growth and fibrosis –Increased sodium reabsorption –Decreased renal blood flow  Adrenal Glands –Increased formation of aldosterone  Coagulation System –Increased fibrinogen –Increased PAI-1 (plasminogen activator inhibitor-1) relative to tissue plasminogen factor Adapted from Opie and Gersh. Drugs for the Heart, Potential Pathogenic Properties of Angiotensin II (continued)

9 Aldosterone Sympathetic activation Growth factor stimulation NA + retention H 2 O retention K + excretion Mg + excretion Vascular smooth muscle constriction Angiotensin converting enzyme (ACE) Angiotensin II Liver secretes angiotensinogen Kidneys secrete renin The Renin-Angiotensin-Aldosterone (RAA) System Angiotensinogen Angiotensin I Adrenal cortex secretes aldosterone BloodRenin

10 RAA System Pathways to Target Receptor Sites Aldosterone Angiotensinogen Angiotensin IAngiotensin II CE Renin Chymase Bradykinin Inactive K+K+ Na + ACTH Other Adrenal Vascular Myocardial Renal CNS

11 Losartan Atenolol (n=4,605)(n=4,588) RR (%) p-value Primary composite † CV mortality Stroke MI Total mortality New onset DM ‡ <.001 LIFE: Primary and Select Secondary Outcomes Adjusted* * For degree of LVH and Framingham risk score at randomization † Number of patients with a first primary event ‡ In patients without diabetes at randomization (losartan, n=4,019; atenolol, n=3,979) Adapted from B Dahlöf et al. Lancet. 2002;359:

12 -22 (P<.001) MI, Stroke, CV Death (primary end point) -26 (P<.001) CV Death -20 (P<.001) MI -32 (P<.001) Stroke -16 (P=.005) All-cause Death Risk Reduction (%) HOPE: Risk Reduction of CV Events Associated with ACEI (RAS Inhibition) Treatment Adapted from The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin- converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:

13 Mechanism of Action of Angiotensin II Receptor Antagonists Angiotensinogen Angiotensin I Angiotensin II AT 2 receptor AT 1 receptor Other AT receptors Bradykinin Inactive peptides Vasodilation Attenuate growth and disease progression ACE inhibitors Alternate pathways AIIRAs ? ?

14 Val-HeFT Results Overall mortality was similar in the two groups 13% RRR (p=.009) in combined end point Predominantly because of a 27% decrease in hospitalization for HF in the valsartan group Subgroup analyses: –Valsartan had a favorable effect in patients receiving neither an ACE inhibitor nor a beta- blocker –Valsartan had a favorable effect in patients receiving an ACE inhibitor or a beta blocker –Valsartan demonstrated a statistically non- significant trend towards an adverse outcome in patients receiving an ACE inhibitor and a beta blocker

15 ADA Guidelines on Management of Diabetic Nephropathy Hypertensive Type 2 Diabetic Patients* ARBs are the initial agents of choice Type 1 Diabetics with or without hypertension* ACEIs are the initial agents of choice If one class is not tolerated the other should be substituted * With microalbuminuria and clinical proteinuria. Adapted from American Diabetes Association. Diabetes Care. 2002;25:S85-S89.

16 Effect of ACE Inhibition on Nephropathy in Type 1 Diabetes * P=.006 vs placebo. Adapted from Lewis EJ et al. N Engl J Med. 1993;329: Adapted from Lewis EJ et al. N Engl J Med. 1993;329: Progression to Death, Dialysis, or Transplant (%) Captopril Placebo Follow-up (y) *

17 ACE Inhibitors and ARBs Captopril Enanlapril Lisinopril Ramipril Perindopril Quinapril Losartan Irbesartan Candesartan Valsartan Telmisartan Olmesartan Aliskiren

18 Proven role of Beta Blockers in Various Indications - Hypertension - Diabetes Mellitus - CHF - CAD

19 Kjekshus J et al. Eur Heart J 1990; 11: Effect of Beta-Blockers on mortality following myocardial infarction Effect of Beta-Blockers on mortality following myocardial infarction Diabetes mellitus, all Diabetes mellitus, beta-blocker No diabetes mellitus, no beta-blocker No diabetes mellitus, beta-blocker 1 year-mortality (%) Diabetes mellitus, no beta-blocker No diabetes mellitus, all

20 Jonas et al. Am J Cardiol 1996; 77: 1273 et seqq. Usefulness of beta-blocker therapy in patients With Diabetes Mellitus and CAD (BIP) Usefulness of beta-blocker therapy in patients With Diabetes Mellitus and CAD (BIP) Year Withoutß-blockers Withß-blockers P= Survival rate

21 Effect of Beta-Blockers on Mortality in Heart Failure Patients 34% lower risk (0.53– 0.81) P= after adjusted interim analysis MERIT-HF (metoprolol) 34% lower risk P< CIBIS-II (bisoprolol) 38% lower risk (18%-53%) P< US Carvedilol 35% lower risk* COPERNICUS (carvedilol) 8.5% lower risk P=NS BEST (bucindolol) Clinical Trial All-cause mortality Combined end point: risk of hospitalization or death All-cause mortality Trial End Point Risk Reduction, % (95% CI) *Preliminary data from XXII Congress of the European Society of Cardiology

22 Effects of Metoprolol CR and Placebo on Neurohormonal Activation * * 34.3 Placebo Metoprolol NS Plasma renin ng/ml Angiotensin II pg/ml Aldosterone pg/ml Plasma renin ng/ml Angiotensin II pg/ml Aldosterone pg/ml Baseline 24 weeks Baseline 24 weeks *P<0.05 NS: Non Significant The Resolvd Investigators

23 Mega-trials on: metoprolol, bisoprolol, carvedilol & bucindolol. Consistent good results in mild / moderate HF. Significant ↓ in rate of hospitalisation. Fair improvements in symptoms & QOL. Improvements in hemodynamics of HF & remodeling. Results in severe HF are not uniform. Bucindolol in BEST showed no benefits. Sub-analysis of CIBIS-II (Bisoprolol) & MERIT-HF: ↓ benefits in more severe HF. COPERNICUS: significant benefits in severe HF. Effect of  -Blocker in Heart Failure

24 Lipophilic beta blockers are an ideal choice in patients at high risk of SCD, prior MI, HT,CHF

25 Beta Blockers Propranolol Atenolol Metoprolol( Sustained Release) Bisoprolol Carvedilol

26 Diuretics ALLHAT Because of the superiority of thiazide-type diuretics in preventing one or more major forms of CVD and their lower cost, they should be the drugs of choice for first-step antihypertensive drug therapy. Hydrochlorthiazide Metolazone Furosemide Torsemide Amiloride

27 Calcium Channel Blockers F Very effective in lowering BP F Safe F OD or BID Dose F No significant outcome benefits F Peripheral edema Nifedipine(Long Acting) Amlodepine Verapamil Nicardepine Lercanidipine Felodepine

28 Miscellaneous Direct Vasodilators – Dihydrallazine – Minoxidil – Prazosin Central Alpha Agonists – Clonidine – Moxolidine Aldosterone antagonists – Spironolactone – Eplerenone Indapamide

29 Benefits of Lowering BP Average Percent Reduction Stroke incidence 35–40% Myocardial infarction 20–25% Heart failure50%

30 U.S. Department of Health and Human Services National Institutes of Health National Heart, Lung, and Blood Institute The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) National Heart, Lung, and Blood Institute National High Blood Pressure Education Program

31 Blood Pressure Classification Normal<120and<80 Prehypertension 120 – 139 or 80 – 89 Stage 1 Hypertension 140 – 159 or 90 – 99 Stage 2 Hypertension >160or>100 BP ClassificationSBP mmHg DBP mmHg

32 Compelling Indications for Individual Drug Classes Compelling Indication Initial TherapyClinical Trial Basis ACC/AHA Heart Failure Guideline, MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, ValHEFT, RALES ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS ALLHAT, HOPE, ANBP2, LIFE, CONVINCE THIAZ, BB, ACEI, ARB, ALDO ANT BB, ACEI, ALDO ANT THIAZ, BB, ACE, CCB Heart failure Postmyocardial infarction High CAD risk

33 Diabetes Chronic kidney disease Recurrent stroke prevention Compelling Indications for Individual Drug Classes Compelling Indication Initial Therapy Options Clinical Trial Basis NKF-ADA Guideline, UKPDS, ALLHAT NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK PROGRESS THIAZ, BB, ACE, ARB, CCB ACEI, ARB THIAZ, ACEI

34 Cardiovascular Diseases Cerebrovascular disease –Indication for treatment, except immediately after ischemic cerebral infarction. Coronary artery disease –Benefits of therapy well established. Left ventricular hypertrophy –Antihypertensive agents (except direct vasodilators) indicated. –Reduced weight and decreased sodium intake beneficial.

35 Cardiovascular Diseases (continued) Cardiac failure –ACE inhibitors, especially with digoxin or diuretics, shown to prevent subsequent heart failure. Peripheral arterial disease –Limited or no data available.

36  For persons over age 50, SBP is a more important than DBP as CVD risk factor  Starting at 115/75 mmHg, CVD risk doubles with each increment of 20/10 mmHg throughout the BP range.  Persons who are normotensive at age 55 have a 90% lifetime risk for developing HTN.  Those with SBP 120–139 mmHg or DBP 80–89 mmHg should be considered prehypertensive who require health-promoting lifestyle modifications to prevent CVD. New Features and Key Messages

37 JNC-VII New Features and Key Messages (Continued)  Thiazide-type diuretics should be initial drug therapy for most, either alone or combined with other drug classes.  Certain high-risk conditions are compelling indications for other drug classes.  Most patients will require two or more antihypertensive drugs to achieve goal BP.  If BP is >20/10 mmHg above goal, initiate therapy with two agents, one usually should be a thiazide-type diuretic.

38 Preventable CHD Events from Control of Hypertension in US Adults (Wong et al., Am Heart J 2003; 145: ) (cont.) The greatest impact (absolute numbers) from control of hypertension occurs in men, older persons, and those with isolated systolic hypertension The greatest proportion of preventable CHD events from control of hypertension occurs in women Optimal control of blood pressure could prevent more than one third of CHD events in men and more than half of CHD events in women

39 Evolution of Antihypertensive Therapies Direct vasodilators  -blockers VPIs Others Peripheral sympatholytics Ganglion blockers Veratrum alkaloids Central  2 agonists Calcium antagonists- non DHPs  - blockers Thiazides diuretics Calcium antagonists- DHPs ARBs 1940’s ’s1970’s1980’s1990’s2001 ACE inhibitors Effectiveness Tolerability

40 We are still evolving towards finding an Ideal Antihypertensive

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42 Preventable CHD Events from Control of Hypertension in US Adults (Wong et al., Am Heart J 2003; 145: ) PAR% = population attributable risk (proportion of CHD events preventable), NNT = number needed to treat to prevent 1 CHD event ; <0.01 comparing men and women for PAR%

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44 Compelling Indications for Certain Drug Classes

45 HTN with CAD Beta blockers: cardioprotective (reinfarction, arrhythmias and sudden death) ACE inhibitors: MI with systolic dysfunction- heart failure and mortality improved

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47 Aliskiren is a novel, completely nonpeptide, orally active renin inhibitor that blocks the first and rate-limiting step of the renin- angiotensin system Alagebrium, an advanced glycation end product (AGE) crosslink breaker, has been shown to reduce SBP in patients with uncontrolled systolic hypertension, progestin drospirenone and 17beta-estradiol (DRSP/E2), developed for postmenopausal hormone replacement therapy, has been shown to lower both clinic and ambulatory SBP in postmenopausal women

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49 Adapted from: Eichhorn EJ, Bristow MR. Circulation. 1996;94: Pathophysiology of Heart Failure Cell death Altered gene expression Growth and remodeling Ischemia and energy depletion Activation of RAA System, SNS, and cytokines Increased load Cardiac injury Direct toxicity ApoptosisNecrosis Reduced systemic perfusion

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51 Pathogenesis of HT Reasons are mulitfactorial.. Renin Angiotensin II Angiotensin I Increased Na + & water reabsorption Vasoconstriction

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53 Summary


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