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ACE Inhibitors ACE = Angiotensin I Converting Enzyme 10 ACE inhibitors available in US:  benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril,

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Presentation on theme: "ACE Inhibitors ACE = Angiotensin I Converting Enzyme 10 ACE inhibitors available in US:  benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril,"— Presentation transcript:

1 ACE Inhibitors ACE = Angiotensin I Converting Enzyme 10 ACE inhibitors available in US:  benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril. ACE inhibitors were the 4 th most prescribed drug class in the U.S (159.8 million Rx in 2008). Lisinopril was the 2 nd most prescribed drug in the US (75.5 million Rx in 2008).

2 The Renin-Angiotensin and Kallikrein-Kinin Systems From: Skidgel RA and Erdös EG, Hypertension Primer, 4 th Edition, Chap. A15, 2008.

3 Peptide Hormone Processing and Drug Development Strategies Prohormone Peptidase 1 Endoprotease Active Peptide Processing Enzyme Receptor 1 Receptor 2 Peptidase 2 Block Activity Enhance Activity Block Activity

4 ACE ACE DISTRIBUTION Widespread, concentrated on: Endothelial surface of the vasculature Epithelial Brush borders Renal proximal tubules Small intestine Placenta Choroid plexus

5 ACE can cleave a variety of peptides

6 Structures of Clinically Used ACE Inhibitors

7 Regulation of Renin Release: Renal Baroreceptor - senses pressure in wall of afferent arteriole; decrease stimulates renin secretion Macula Densa – senses chronic change in distal tubule salt delivery; decrease induces renin release. Sympathetic Nerves – JG cells are directly innervated by sympathetic nerves; stimulation increases renin secretion Angiotensin II- stimulates AT1 receptors on JG cells to decrease renin release

8 Angiotensinogen Renin Angiotensin I (Inactive) Blood Pressure Kininogen Kallikrein Bradykinin Kinin B2 Receptor Vasodilation Na+ Excretion Bradykinin(1-7) (Inactive) ACE Inhibitors Mechanism of Action of ACE Inhibitors Angiotensin II AT1 Receptor Vasoconstriction Aldosterone release Na+ Retention Pro-inflammatory Oxidative stress Proliferation of Sm. muscle/myocytes Liver Chymase Cathepsin G

9 Angiotensinogen Renin Angiotensin I (Inactive) Angiotensin II AT1 Receptor Blood Pressure Endopeptidases Angiotensin 1-7 AT 1-7 /Mas Receptor Angiotensin 1-5 (Inactive) ACE Inhibitors Mechanism of Action of ACE Inhibitors II Vasodilation Na+ Excretion Anti-inflammatory Oxidative stress Vasoconstriction Aldosterone release Na+ Retention Pro-inflammatory Oxidative stress Proliferation of Sm. muscle/myocytes

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12 Clinical Use of ACE Inhibitors Antihypertensive  ~ 50% response (~90% with diuretic)  ↓Systemic Vascular Resistance  ↓Stress or Relfex induced sympathetic stimulation  → Heart rate  ↑ Sodium excretion, ↓ Blood volume Congestive Heart Failure  ↓Vascular Resistance, Blood volume, Heart rate  ↑ C.O. (no change in myocardial O 2 consumption) Diabetic Nephropathy  Dilates afferent and efferent renal arterioles  ↓Glomerular capillary pressure  ↓Growth of mesangial cells/matrix due to Ang II?

13 Side Effects/Contraindications Common  Dry Cough  5 – 20% of patients  Not dose-related; occurs within 1 wk. – 6 mo.  Women > men  May Require cessation of therapy  Fetopathic Potential  Not teratogenic in 1st trimester  Developmental defects in 2nd or 3rd trimester Rare  Angioneurotic Edema (or Angioedema)  ~ % of patients  Not dose-related; occurs within 1 st week  Severe swelling of mouth, tongue, lips, airway  may be life-threatening

14 Angioedema

15 Side Effects/Contraindications Rare  Hypotension  First dose effect in patients with elevated PRA, salt depletion, CHF  Hyperkalemia  In patients with renal insufficiency, diabetic nephropathy  Acute Renal Failure  Patients with renal stenosis, heart failure, volume depleted  Skin Rash Extremely Rare (reversible)  Alteration/loss of taste  Neutropenia  Glycosuria  Hepatotoxicity

16 Drug Interactions  Antacids  May reduce bioavailability of ACE inhibitors  Capsaicin  May worsen ACE inhibitor-induced cough  NSAIDs  May reduce antihypertensive response to ACE inhibitors  K + -sparing Diuretics or K + supplements  May exacerbate ACE inhibitor-induced hyperkalemia

17 Additional Beneficial Effects of ACE Inhibitors Cardioprotective Reduce incidence of second heart attack Reduce cardiovascular complications in patients with risk factors Reduce incidence of diabetes in high risk patients Reduce complications in diabetic patients

18 ACE Angiotensinogen Renin Angiotensin I (Inactive) Bradykinin B2 Receptor AT1 Receptor Angiotensin II Bradykinin(1-7) (Inactive) Blood Pressure ARBs Angiotensin (AT1R) Receptor Blockers (“ARBs” or “sartans”) AT2 Receptor AT1 Receptor Vasoconstriction Aldosterone release Na+ Retention Pro-inflammatory Oxidative stress Proliferation of Sm. muscle/myocytes Vasodilation Na+ Excretion Anti-inflammatory Anti-proliferative Chymase Cathepsin G

19 Clinical Use of Angiotensin Receptor Blockers Effects are Similar to those of ACE inhibitors FDA Approved for: Hypertension  All ARBs Congestive Heart Failure  Valsartan approved (second line therapy if ACE inhibitors not tolerated) Diabetic Nephropathy  Irebesartan and Losartan (some believe superior to ACE inhibitors)

20 Side Effects/Contraindications  Better tolerated than ACE inhibitors  Much reduced risk of cough  >2-fold lower risk of Angioedema  Other side effects, including fetopathic potential, the same as for ACE inhibitors

21 Renin Inhibitor ACE Kininogen Angiotensinogen Renin Kallikrein Angiotensin I (Inactive) Bradykinin B2 Receptor AT1 Receptor Angiotensin II Bradykinin(1-7) (Inactive) Blood Pressure Renin Inhibitor Aliskiren Vasodilation Na+ Excretion AT1 Receptor Vasoconstriction Aldosterone release Na+ Retention Pro-inflammatory Oxidative stress Proliferation of Sm. muscle/myocytes Chymase Cathepsin G

22 Clinical Use of Aliskiren (Renin Inhibitor) FDA Approved for Hypertension  Currently being tested for use in Congestive Heart Failure and Diabetic Nephropathy Side Effects/Contraindications  Generally well tolerated  Teratogenic  Low risk of cough and angioedema  Most common side effects (<5%):  Gastrointestinal disturbance  Headache/dizziness  Hyperkalemia  Rash (rare)


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