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 Ø Phosphorus-containing: fosinopril sodium Ø Ø Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 2

Drug Overview Angiotensin II Receptor Blockers Ø losartan, candesartan, eprosartan, irbesartan, olmesartan, telmisartan, valsartan Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 3

Indications Labeled Uses: ACEIs Ø Unlabeled Uses: ACEIs Ø HTN, CHF, MI, left ventricular dysfunction, diabetic neuropathy Captopril: Hypertensive crisis In General, ACEIs and ARBs Are Equally Effective Both Classes Lack Serious Adverse Reactions Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 4

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 Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 5

Mechanism of Action ACEIs Block Angiotensin-Converting Enzyme (ACE) ACE: Responsible for the conversion of angiotensin I to angiotensin II Ø Angiotensin II: Potent vasoconstrictor and stimulus for aldosterone release from adrenal glands Ø Reduction in aldosterone results in less water absorption and sodium/potassium exchange in the distal renal tubule • Causing a slight increase in serum potassium Ø Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 6

Mechanism of Action ACEIs Inhibit Breakdown of Bradykinin (Vasodilator) by Blocking the Enzyme Kinase II Ø Thought to be the cause of cough SE ARBs Block Effects of Angiotensin II by Blocking the Binding of Angiotensin II to Its Receptors Ø Ø Do not affect bradykinin Receptor affinity is highest by candesartan > irbesartan > eprosartan > telmisartan > valsartan > losartan Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 7

Mechanism of Action ARBs Differ from ACEIs in Some Respects ARBs are more active against AT 1 receptors than are ACEIs Ø ACE inhibition is not associated with increased levels of angiotensin II Ø ACEIs may increase angiotensin levels to a greater extent than ARBs Ø ACEIs increase levels of bradykinin Ø Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 8

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 Ø Renal perfusion is increased Ø Renal vascular resistance is decreased Ø GFR is unchanged Ø Ø Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 9

Mechanism of Action ACE Inhibition in Patients with CHF Significant decrease in preload through reduction in sodium and water retention Ø 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 Ø volume Ø Improvement in myocardial energy metabolism Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 10

Mechanism of Action ACE Inhibition in Patients with Renal Impairment Reduction in arteriolar resistance • Improvement in renal hemodynamics Ø May improve course for patients with diabetic nephropathy and other renal diseases with glomerular hypertension Ø Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 11

Treatment Principles ACEIs and ARBs Have a Low Incidence of Adverse Reactions All ACEIs Have Similar Therapeutic Action and Adverse Reactions Ø Ø Some are prodrugs Duration of action may differ Tissue distribution may differ Most are excreted renally Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 12

Treatment Principles Generally considered safe in patients with mild to moderate renal impairment Ø 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 Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 13

Treatment Principles Advantages of ARBs Over ACEIs Ø Ø Ø No dry cough Decreased incidence of angioedema Second-line treatment because of cost Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 14

Treatment Principles Hypertension Ø Useful in treatment of HTN with concomitant illnesses • DM, renal insufficiency, left ventricular dysfunction, CHF Ø Ø 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 Ø BP reduction may be progressive with maximal results in 2 to 4 weeks Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 15

Treatment Principles Hypertension (cont’d) BP reduction may be progressive with maximal results in 2 to 4 weeks Ø Regression of left ventricular hypertrophy Ø ALLHAT trial • ACEI was less cardioprotective than thiazide Ø diuretics Ø No effect on glucose, cholesterol, or uric acid levels Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 16

Treatment Principles Hypertension (cont’d) Studies show an increase in insulin sensitivity and a modest reduction in plasma glucose Ø Minimize or prevent diuretic-induced elevations in cholesterol and uric acid levels Ø Seven trials found that risk of developing DM was 22% less than that of other agents or placebo Ø Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 17

Treatment Principles Hypertension (cont’d) Ø Three trials (DREAM, NAVIGATOR, and ONTARGET) are under way • To determine whether ACEIs and ARBs or combination therapy is more effective in preventing DM Ø Antihypertensive effects of ARBs are comparable with those of ACEIs Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 18

Treatment Principles Post–Myocardial Infarction/High Risk of Cardiovascular Events Ø ACEIs • Preventricular 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 Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 19

Treatment Principles Post–Myocardial Infarction/High Risk of Cardiovascular Events Ø 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 Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 20

Treatment Principles Post–Myocardial Infarction/High Risk of Cardiovascular Events Ø 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 Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 21

Treatment Principles Post–Myocardial Infarction/High Risk of Cardiovascular Events Ø 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 Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 22

Treatment Principles Post–Myocardial Infarction/High Risk of Cardiovascular Events Ø 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 Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 23

Treatment Principles Chronic Heart Failure Ø 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 Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 24

Treatment Principles Chronic Heart Failure (cont’d) Patient should be well hydrated prior to initiation of ACEI to avoid renal failure Ø Meta-analysis of more than 12, 000 patients • Reduced total mortality • Lower hospital readmissions • Reduction in incidence of MI Ø ARB use in HF may be as effective as or slightly less effective than ACEIs • 2005 ACC/AHA task force recommends ARBs Ø inpatients who cannot tolerate ACEIs Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 25

Treatment Principles Chronic Heart Failure (cont’d) Ø Benefits of ACEIs in the African American population have not been strong • V-He. FT and SOLVD found higher rates of progressive HF and overall mortality in this population Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 26

Treatment Principles Prevention of Renal Failure in DM Ø 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 Ø American Diabetes Association 2004 Statement on the Use of ACEIs and ARBs Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 27

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 Ø No risk factors for renal deterioration: Recheck every 3 to 6 months Ø Ø Ø Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 28

How to Monitor Baseline and Periodic (cont’d) Ø Ø Supine BP weekly while titrating Angioedema without urticaria • 50% of cases develop within 1 week of initiation Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 29

Patient Variables Geriatrics Lower dose may be needed in patients with renal or hepatic insufficiency Ø Useful in elderly Ø Pediatrics Ø Ø Safety and efficacy have not been established Irbesartan is indicated in children older than 6 years Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 30

Patient Variables Pregnancy Ø 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 Ø Use in combination with diuretics has been successful in this population Ø Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 31

Patient Education Do Not Take Two Doses at the Same Time Common SEs Include: Ø Ø 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 Ø Irregular HR, leg weakness, numbness/tingling in hands or feet, extreme nervousness Ø Avoid Use of Potassium-Containing Medicines or Salt Substitutes While on This Medication Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 32

Lisinopril Contraindications Warnings Ø First-dose effect Precautions Mosby items and derived items © 2009,

Lisinopril: Pharmacokinetics See Table 20 -2 Mosby items and derived items © 2009, 2004

Lisinopril: Adverse Effects See Table 20 -3 Mosby items and derived items © 2009,

Lisinopril: Drug Interactions See Table 20 -4 Mosby items and derived items © 2009,

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 Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 37

Lisinopril: Dosage and Administration Decrease Dose in Patients with Renal Insufficiency: lisinopril, captopril, enalapril, ramipril Mosby items and derived items © 2009, 2004 by Mosby, Inc. , an affiliate of Elsevier Inc. 38