Transcript Document
The Renin-Angiotensin System 1. ↓ Renal Perfusion Pressure 2. ↓ Na at Macula Densa cells 3. ↑ Sympathetic nerve activity (ß-1) Non-ACE (eg. Chymase in heart) Angiotensinogen ±PG + NH2-Asp-Arg-Val…Pro-Phe-Hist-Leu…COOH 1 2 3 7 8 9 10 Renin Angiotensin I NH2-Asp-Arg-Val…Pro-Phe-COOH 1 2 3 7 8 9 10 ACE Angiotensin II NH2-Asp-Arg-Val…Pro-Phe-COOH 1 2 3 7 8 Aminopeptidase Angiotensin III Angiotensin 1-7 Releases ADH; ↑ PG; Natriuretic; ↓ RVR; ↓ BP (brain stem inj.) ? Role in effects of ACEI NH2-Arg-Val…Pro-Phe-COOH 2 3 7 8 ANGIOTENSIN II - SUPPORT OF THE BLOOD PRESSURE Cardiac & Vascular Hypertrophy ↑ Cardiac Contractility Sympathetic Facilitation: Central Nerve terminal (ganglionic ?) Vasoconstriction Direct Renal Sodium Retention Angiotensin II Aldosterone Secretion ↑ Thirst ADH Release All known physiologic effects are mediated by the angiotensin II type 1 receptor Angiotensin Converting Enzyme Inhibitors Large number of drugs available differ mainly in the following: 1. Potency Route of elimination Duration of action Being prodrugs or active drugs 2. 3. 4. Similar therapeutic indications, adverse effects and contraindications Adverse Effects • Hypotension • Renal Insufficiency (if bilateral renal artery stenosis) • Hyperkalemia – special group of patients (Na restricted, on K-sparing diuretic, COX inhibitors) • Cough (20 %) Kinin-related (?) • Angioedema • With captopril especially: neutropenia, nephrotic syndrome, skin rash, taste disturbances (SH grouprelated). Binds to Zn ion Binds to active site Enalapril Binds more strongly to Zn – more active Lisinopril ACE Inhibitors and Left Ventricular Hypertrophy ACE Inhibitors and Left Ventricular Hypertrophy ACE Inhibitors after Myocardial Infarction ACE Inhibitors in Heart Failure Study of LV Dysfunction (SOLVD) Asymptomatic Patients with EF<40% ACE Inhibitors in Severe Heart Failure Probability of Sudden Death Placebo Captopril Probability of Survival Mortality Rate Survival and Ventricular Enlargement Trial (SAVE) Captopril Hydralazine Patients with Severe Heart Failure Placebo Enalapril Cooperative New Scandinavian Enalapril Survival Study (CONSENSUS) Enalapril Metoprolol Metoprolol Enalapril ACE Inhibitors – Effect on Progression of Diabetic Nephropathy ACE Inhibitors – Effect on Progression of Non-Diabetic Nephropathy Therapeutic Uses • Anti-hypertensive • Prevent or reverse LVH • Protect against sudden death and second myocardial infarction after acute MI • Improve survival and hemodynamics in patients with congestive heart failure • Protect against progression of diabetic and non-diabetic nephropathy Angiotensin II Type 1 Receptor Blockers Losartan Valsartan Candesartan Angiotensin Receptor Blockers e.g. Losartan • Block only the AT-1 subtype • Comparable effects to ACE Inhibitors in almost all situations. • Less decrease in GFR in volume depleted states Kinins • Less side effects especially cough, angioedema, (?) rash • Block all AII effects and not dependent on particular pathway 3 month mortality (%) P: Placebo E: Enalapril L: Losartan C: Captopril P E P L SOLVD US +Int’l Exercise (n=2569) (n=736) C L ELITE (n=722) Fig. 3: 3-month mortality in three different studies ELITE STUDY GROUP (Evaluation of Losartan in the Elderly) – Losartan better than captopril in patients with heart failure (chance finding?) ELITE STUDY GROUP Losartan Superior to Captopril (? Chance Finding) Probability of Survival Losartan Captopril Follow-up (days) ELITE II STUDY GROUP (3,152 patients for 1.5 y) No Difference between Captopril and Losartan Probability Of Survival % Event-free Probability % Lancet. 2000;355:1582-7. Hypertensive Patients with Nephropathy AII Receptor Blocker ACE Inhibitor Blocks formation Blocks Kininase II of AII incompletely ↓ AII effects & aldosterone Blocks AT-1R AT-2R Free ↑ Kinins More complete Preserve Inhibition of AII effects PROTECTION Antiproliferative effect