LXIV: DRUGS: 4. RAS BLOCKADE

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1 LXIV: DRUGS: 4. RAS BLOCKADE ACE Inhibitors Components of RAS Actions of Angiotensin i II Indications for ACEIs Contraindications RAS blockade in hypertension RAS blockade in CAD RAS blockade in HF Limitations and adverse reactions

2 Renin-Angiotensin Systems (I) Classical "circulating" system (RAAS): Angiotensin II glomerular zone adrenal glands ACE Aldosterone Angiotensin I Renin Renin Na + retention K + loss Angiotensinogen macula densa BP Na Vol + Sympathetic system adapt. from Dominiak & Unger (eds.) in Ang II-AT1-Receptor Antagonists, Steinkopff (1997) Renin-Angiotensin Systems (III) Distribution of ACE: 10 % R A S 90 % circulating (plasma) local (tissue) Acute and short-term effects cardiovascular/ renal homeostasis Long-term effects local "organ adaptation" renal-independent activation mod. from Dzau V, Arch Intern Med 153 (1993)

3 Angiotensin-II BLOOD PRESSURE HOMEOSTASIS Blood vessels Blood volume PROINFLAMMATORY AND HEMOSTATIC FUNCTIONS Indications Hypertension Coronary artery disorders Heart failure

4 Materson et al. NEJM, % 20 EHS EGYPTIAN HYPERTENSION SOCIETY DRUG THERAPY MULTICENTER STUDY- 429 Patients PECENTAGE OF PATIENTS WITH CONTROLLED BP Diuretic B- Blocker ACE-I Ca-C Bl Total

5 RAS Blockade in Hypertension Specific Indications Heart failure due to systolic dysfunction Chronic renal failure, both diabetic and nondiabetic After a myocardial infarction High risk patients (associated CVD, diabetes with CVRF) LVH Elderly hypertensives Indications Hypertension Coronary artery disease Heart failure

6 Indications of ACE-Inhibitors in Coronary Artery Disease Impaired LV systolic function Acute coronary syndromes Chronic stable angina in high risk patient Prevention of coronary events in high risk patients Rationale of ACE-Inhibitors in Coronary Artery Disease Anti-ischemic effects Anti-atherosclerotic potential Anti-thrombotic effects Plaque stabilizing i effects

7 ACE-Inhibitors Anti-Ischemic Effects HEMODYNAMIC O2 demand: - negative inotropic effect - loading O2 supply: - coronary vasodilation STRUCTURAL EFFECTS Cardiac: Vascular: - hypertrophy - enlargement - endothelium -VSMCs NEUROHORMONAL MODULATION Sympathetic stimulation ACE-Inhibitors Plaque Stabilization Plaque Structure - Inflammation : IL6, MCP-1, CRP - Thrombogenecity : PAI-1, TF Endothelial Function - Oxidative stress - NO synthase expression - Anti-inflammatory, inflammatory Antiplatelet Systemic Milieu - Anti-inflammatory - Anti-thrombotic: TF, PAI-1, platelet activation

8 ACE-Inhibitors Reduction in Myocardial Ischemia Recurrent MI: 23% (SOLVD) - 25% (SAVE) Revascularization: 24% (SAVE) Hospitalization for unstable angina: 20% (SOLVD) ACE-Inhibitors Therapy in AMI Start at low doses soon after MI with careful monitoring of BP Rapid upward titration of the dose (within 7 days) to reach the maximum dose In unstable patients with low BP (SBP < 90 mmhg) captopril is recommended because of its short duration of action

9 ACE-Inhibitors in Post-MI Patients Mode of action: 1 By preventing the production of the vasoconstrictor angiotensin II ACE-inhibitors promote vasodilation and reduce blood pressure ACE-inhibitors favourably affect ventricular remodelling by decreasing stimulation of the neuroendocrine system Initiation of treatment Treatment ideally started within 48 hr and continued indefinitely 2 1. Kloner & Przyklenk (1992) Clin Cardiol 15: ACC/AHA Guidelines (1996) J ACC 28: AHA/ACC 2007 Guidelines for Management of Patients With Chronic Stable Angina ACE inhibitor (eg. Ramipril 10mg qd) in all patients with coronary artery disease, who have also diabetes and/or left ventricular systolic dysfunction Class I Recommendation, Level of evidences: A Circulation. 2003;107:

10 ACE-Inhibitors Which and What Dose? Starting dose Target dose captopril 6.25 mg tid mg tid enalapril lisinopril ramipril 2.5 mg bid mg bid mg qd mg qd 2.5 mg qd trandolapril 1 mg qd perindopril 2 mg qd 5 mg bid/10 mg qd 4 mg qd 2-8 mg qd AHA/ACC 2007 Guidelines on Secondary Prevention Renin-angiotensin-aldosterone system blockers include ACE inhibitors, which should be continued indefinitely in all patients with left ventricular ejection fraction 40% or lower and in those with hypertension, diabetes, or chronic kidney disease, unless contraindicated, and considered for all other patients. Angiotensin receptor blockers should be used in patients who are intolerant of ACE inhibitors and have heart failure or have had a myocardial infarction with left ventricular ejection fraction less than 40%, and they should be considered in other patients intolerant of ACE inhibitors or in combination with ACE inhibitors in systolic-dysfunction heart failure (AHA/ACC 2006 Guidelines Updated on Secondary Prevention for Atherosclerotic Vascular Disease)

11 Indications Hypertension Coronary artery disease Heart failure Indications: ACE-Inhibitors In Whom and When? potentially all patients with heart failure 1st line treatment NYHA class I-IV heart failure Contra-indications: history of angioneurotic oedema Cautions/seek specialist advice: significant renal dysfunction (creatinine > 2.5 mg/dl ) or hyperkalaemia (K + > 5.0 mmol/l) symptomatic or severe asymptomatic hypotension (SBP < 90 mmhg) Drug interactions to look out for: K + supplements/ K + sparing diuretics (including spironolactone) NSAIDs* *avoid unless essential

12 ACE-Inhibitors How to Use Start with a low dose Double dose at not less than 2 weekly intervals Aim for target dose or, failing that, the highest tolerated dose Remember some ACE inhibitor is better than no ACE inhibitor Monitor blood chemistry (urea, creatinine, k + ) and BP at initiation and after 4-8 weeks, then every 3 months ACE-Inhibitors Adverse Reactions Hypotension Renal failure Hyperkalemia Cough Allergic reactions -Skin rash -Angioneurotic edema -Interstitial nephritis (with very big doses)

13 Contraindications Previous history of allergic reaction to ACEI or ARB Bilateral renal artery stenosis Renal artery stenosis to a single functioning kidney Pregnancy Shock or SBP < 80 mmhg ACE-Inhibitors in Heart Failure Worsening Renal Function An increase in creatinine of up to 50% above baseline, or 3 mg/dl (266 µmol/l), whichever is the smaller, is acceptable An increase in K + up to 6.0 mmol/l is acceptable If urea, creatinine or K + rise excessively consider stopping concomitant nephrotoxic drugs and, if no signs of congestion, reducing the dose of diuretic If greater rises in creatinine or K +, halve the dose of ACE inhibitor and recheck blood chemistry; if there is still an unsatisfactory response, specialist advice should be sought

14 ACE-Inhibitors in Heart Failure Worsening Renal Function If K + rises to > 6.0 mmol/l or creatinine increases by >100% or to above 4 mg/dl (354 µmol/l), the dose of ACE inhibitor should be stopped and specialist advice sought Blood chemistry should be monitored serially until K + and creatinine have plateaued NB: it is very rarely necessary to stop an ACE inhibitor and clinical deterioration is likely if treatment is withdrawn