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Chapter 20

Chapter 20. ACE Inhibitors and Angiotensin Receptor Blockers. Drug Overview. Angiotensin-Converting Enzyme Inhibitors Sulfhydryl-containing: captopril Dicarboxylic-containing: linsinopril HCl, benazepril HCl, enalapril maleate, moexipril HCl; perindopril; ramipril; trandolapril

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Chapter 20

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  1. Chapter 20 ACE Inhibitors and Angiotensin Receptor Blockers

  2. Drug Overview • Angiotensin-Converting Enzyme Inhibitors • Sulfhydryl-containing: captopril • Dicarboxylic-containing: linsinopril HCl, benazepril HCl, enalapril maleate, moexipril HCl; perindopril; ramipril; trandolapril • Phosphorus-containing: fosinopril sodium

  3. Drug Overview • Angiotensin II Receptor Blockers • losartan, candesartan, eprosartan, irbesartan, olmesartan, telmisartan, valsartan

  4. Indications • Labeled Uses: ACEIs • HTN, CHF, MI, left ventricular dysfunction, diabetic neuropathy • Unlabeled Uses: ACEIs • Captopril: Hypertensive crisis • In General, ACEIs and ARBs Are Equally Effective • Both Classes Lack Serious Adverse Reactions

  5. Indications • Most Common and Treatment-Limiting Side Effect of ACEIs Is Cough: 20% of All Users • Most Serious AE of ACEIs Is Angioedema • Other Serious SEs of ACEIs and ARBs Include Hyperkalemia, Hypotension, and Acute Renal Failure • Abrupt Withdrawal Has Not Resulted in Rebound Hypertension

  6. Mechanism of Action • ACEIs Block Angiotensin-Converting Enzyme (ACE) • ACE: Responsible for the conversion of angiotensin I to angiotensin II • Angiotensin II: Potent vasoconstrictor and stimulus for aldosterone release from adrenal glands • Reduction in aldosterone results in less water absorption and sodium/potassium exchange in the distal renal tubule • Causing a slight increase in serum potassium

  7. Mechanism of Action • ACEIs Inhibit Breakdown of Bradykinin (Vasodilator) by Blocking the Enzyme Kinase II • Thought to be the cause of cough SE • ARBs Block Effects of Angiotensin II by Blocking the Binding of Angiotensin II to Its Receptors • Do not affect bradykinin • Receptor affinity is highest by candesartan > irbesartan > eprosartan > telmisartan > valsartan > losartan

  8. Mechanism of Action • ARBs Differ from ACEIs in Some Respects • ARBs are more active against AT1 receptors than are ACEIs • ACE inhibition is not associated with increased levels of angiotensin II • ACEIs may increase angiotensin levels to a greater extent than ARBs • ACEIs increase levels of bradykinin

  9. Mechanism of Action • ACE Inhibition Results in Reduction of Systemic Vascular Resistance • No effect or a moderate increase is seen in CO • BP is lowered, and this is not accompanied by changes in HR • Renal perfusion is increased • Renal vascular resistance is decreased • GFR is unchanged

  10. Mechanism of Action • ACE Inhibition in Patients with CHF • Significant decrease in preload through reduction in sodium and water retention • Significant decrease in afterload via decrease in systemic vascular resistance (effects on angiotensin II) • Modest increase in ejection fraction • Decrease in ventricular end-diastolic pressure and volume • Improvement in myocardial energy metabolism

  11. Mechanism of Action • ACE Inhibition in Patients with Renal Impairment • Reduction in arteriolar resistance • Improvement in renal hemodynamics • May improve course for patients with diabetic nephropathy and other renal diseases with glomerular hypertension

  12. Treatment Principles • ACEIs and ARBs Have a Low Incidence of Adverse Reactions • All ACEIs Have Similar Therapeutic Action and Adverse Reactions • Some are prodrugs • Duration of action may differ • Tissue distribution may differ • Most are excreted renally

  13. Treatment Principles • Generally considered safe in patients with mild to moderate renal impairment • Dosage reduction • Fosinopril, lisinopril, and ramipril are eliminated both renally and hepatically • Dehydration and renal insufficiency increase risk of elevated K+ when ACEIs are initiated

  14. Treatment Principles • Advantages of ARBs Over ACEIs • No dry cough • Decreased incidence of angioedema • Second-line treatment because of cost

  15. Treatment Principles • Hypertension • Useful in treatment of HTN with concomitant illnesses • DM, renal insufficiency, left ventricular dysfunction, CHF • 50% to 60% of whites respond well • African American patients do not respond as well • Addition of low-dose thiazide diuretic provides efficacy comparable with that of whites • BP reduction may be progressive with maximal results in 2 to 4 weeks

  16. Treatment Principles • Hypertension (cont’d) • BP reduction may be progressive with maximal results in 2 to 4 weeks • Regression of left ventricular hypertrophy • ALLHAT trial • ACEI was less cardioprotective than thiazide diuretics • No effect on glucose, cholesterol, or uric acid levels

  17. Treatment Principles • Hypertension (cont’d) • Studies show an increase in insulin sensitivity and a modest reduction in plasma glucose • Minimize or prevent diuretic-induced elevations in cholesterol and uric acid levels • Seven trials found that risk of developing DM was 22% less than that of other agents or placebo

  18. Treatment Principles • Hypertension (cont’d) • Three trials (DREAM, NAVIGATOR, and ONTARGET) are under way • To determine whether ACEIs and ARBs or combination therapy is more effective in preventing DM • Antihypertensive effects of ARBs are comparable with those of ACEIs

  19. Treatment Principles • Post–Myocardial Infarction/High Risk of Cardiovascular Events • ACEIs • Prevent ventricular remodeling and improve endothelial function after MI • Decrease action of fibrin • 2004 ACC/AHA Guidelines recommend that ACEIs should be initiated within 24 hours for patients who are stable with STEMI

  20. Treatment Principles • Post–Myocardial Infarction/High Risk of Cardiovascular Events • ACEIs (cont’d) • Should be avoided in patients with • ACEI allergy • Renal failure • Hypotension (sys BP 90 to 100 mm Hg or 30 mm Hg below baseline) • Shock • H/O bilateral renal artery stenosis • Prior worsening of renal function with ACEIs

  21. Treatment Principles • Post–Myocardial Infarction/High Risk of Cardiovascular Events • ACEIs (cont’d) • Clinically proven to improve survival in patients with serum creatinine concentrations above 3 mg/dl • Study: 20,000 patients 65 years of age who had an MI and impaired LVF and those on ASA

  22. Treatment Principles • Post–Myocardial Infarction/High Risk of Cardiovascular Events • ACEIs (cont’d) • HOPE trial: Landmark study of patients at high risk of cardiovascular events • Trial halted after 4.5 years because ramipril was shown to reduce the following events: • Primary endpoint • Cardiovascular mortality • Nonfatal MI • Stroke • New cases of DM

  23. Treatment Principles • Post–Myocardial Infarction/High Risk of Cardiovascular Events • ACEIs (cont’d) • HOPE trial • Benefit was seen within the first year • Benefit independent of age and gender • Benefits were apparent in patients with significant comorbidities • Benefits were comparable with those seen in trials of statin drugs • Trials done on ACEIs, but it is felt that ARBs would deliver comparable results

  24. Treatment Principles • Chronic Heart Failure • ACEIs should be given to all patients with asymptomatic or symptomatic heart failure • Reduction in ventricular dilation • Restoration of heart muscle to normal elliptical shape • Reverse ventricular remodeling • Reduce preload, afterload, HR, systemic BP, and renovascular resistance • Increase renal blood flow

  25. Treatment Principles • Chronic Heart Failure (cont’d) • Patient should be well hydrated prior to initiation of ACEI to avoid renal failure • Meta-analysis of more than 12,000 patients • Reduced total mortality • Lower hospital readmissions • Reduction in incidence of MI • ARB use in HF may be as effective as or slightly less effective than ACEIs • 2005 ACC/AHA task force recommends ARBs inpatients who cannot tolerate ACEIs

  26. Treatment Principles • Chronic Heart Failure (cont’d) • Benefits of ACEIs in the African American population have not been strong • V-HeFT and SOLVD found higher rates of progressive HF and overall mortality in this population

  27. Treatment Principles • Prevention of Renal Failure in DM • ACEIs and ARBs have been shown to slow progression of diabetic nephropathy • Most trials have been done with the use of ACEIs; ARBs are felt to have similar efficacy • These medications are indicated for all diabetic patients with microalbuminuria or macroalbuminuria • American Diabetes Association 2004 Statement on the Use of ACEIs and ARBs

  28. How to Monitor • Baseline and Periodic • Electrolyte panel • Serum blood urea nitrogen and creatinine • UA • WBC • Once stable: Recheck serum creatinine and potassium at 2 and 4 weeks • No risk factors for renal deterioration: Recheck every 3 to 6 months

  29. How to Monitor • Baseline and Periodic (cont’d) • Supine BP weekly while titrating • Angioedema without urticaria • 50% of cases develop within 1 week of initiation

  30. Patient Variables • Geriatrics • Lower dose may be needed in patients with renal or hepatic insufficiency • Useful in elderly • Pediatrics • Safety and efficacy have not been established • Irbesartan is indicated in children older than 6 years

  31. Patient Variables • Pregnancy • ACEIs and ARBs are associated with significant fetal risk • CV and CNS abnormalities documented in more than three and five times as many infants exposed to ACEIs in the first trimester • Race • Less effective in blacks when used as monotherapy • Use in combination with diuretics has been successful in this population

  32. Patient Education • Do Not Take Two Doses at the Same Time • Common SEs Include: • Nonproductive cough • Dizziness or light-headedness • Red Flags • Swelling, SOB, difficulty swallowing, hives, urticaria, fainting, cloudy urine, sore throat, fever and sudden onset of abdominal pain, diarrhea and vomiting • Irregular HR, leg weakness, numbness/tingling in hands or feet, extreme nervousness • Avoid Use of Potassium-Containing Medicines or Salt Substitutes While on This Medication

  33. Lisinopril • Contraindications • Warnings • First-dose effect • Precautions

  34. Lisinopril: Pharmacokinetics • See Table 20-2

  35. Lisinopril: Adverse Effects • See Table 20-3

  36. Lisinopril: Drug Interactions • See Table 20-4

  37. Lisinopril: Dosage and Administration • 2 Weeks for BP Reduction to Be Seen, and 4 Weeks for Full Effect • Food Affects Rate But Not Extent of Absorption of Fosinopril • Captopril and Moexipril Are Taken 1 Hour Before Meals • Ramipril Caps Can Be Opened and Mixed with Food • Rate and Absorption of Quinapril Reduced by 25% When Taken with High-Fat Meal

  38. Lisinopril: Dosage and Administration • Decrease Dose in Patients with Renal Insufficiency: lisinopril, captopril, enalapril, ramipril

  39. Lisinopril: Dosage and Administration • See Table 20-5

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