1 / 26

Randal A. Skidgel

ACE Inhibitors. Randal A. Skidgel. From: Skidgel and Erdös , AHA Hypertension Primer, 2008. ACE Inhibitors. ACE = Angiotensin I Converting Enzyme 10 ACE inhibitors available in US:

lou
Download Presentation

Randal A. Skidgel

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. ACE Inhibitors Randal A. Skidgel From: Skidgel and Erdös, AHA Hypertension Primer, 2008

  2. 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 4th most prescribed drug class in the U.S (159.8 million Rx in 2008). • Lisinopril was the 2nd most prescribed drug in the US (75.5 million Rx in 2008).

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

  4. Some Biologically Active Peptides

  5. Scheme of Peptide Hormone Processing & Metabolism Receptor 1 RK RR Prohormone Endoprotease Processing Enzyme Active Peptide Peptidase 1 Peptidase 2 Receptor 2

  6. Strategies for Developing Therapeutic Agents Receptor 1 Administer the Peptide Active Peptide Peptidase 1 Peptidase 2 Receptor 2

  7. Use of Peptides as Drugs • Advantages • Highly potent/excellent specificity • Wide variety of Biological Activities • Straightforward Synthesis • Predictable Chemistry • Little or no toxicity from metabolism • Disadvantages • Oral administration difficult because of: • Degradation by digestive enzymes and intestinal peptidases • Poor absorption across tight junctions in epithelila • Efflux systems may pump absorbed peptides back out • Inconvenient administration • Rapidly cleaved by peptidases • Excreted by kidney • Relatively expensive to synthesize compared with small organic molecules

  8. Strategies for Developing Therapeutic Agents Receptor 1 Block Degradation by Peptidases Peptidase 1 Peptidase 2 Receptor 2

  9. Strategies for Developing Therapeutic Agents Use a Receptor Antagonist Active Peptide Peptidase 1 Peptidase 2 Receptor 1 Receptor 2

  10. Strategies for Developing Therapeutic Agents Receptor 1 RK RR Prohormone Endoprotease Block Synthesis/Processing Processing Enzyme Active Peptide Peptidase 1 Peptidase 2 Receptor 2

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

  12. Structure of Human Angiotensin Converting Enzyme (ACE) ACE N-domain ACE C-domain

  13. A given peptidase can cleave a variety of peptides Example: Angiotensin Converting Enzyme (ACE)

  14. Structures of Clinically Used ACE Inhibitors

  15. ACE Inhibitors ACE AT1 Receptor Vasoconstriction Aldosterone release Na+ Retention Pro-inflammatory Oxidative stress Blood Pressure Mechanism of Action of ACE Inhibitors Angiotensinogen Kininogen Kallikrein Renin Kinin B2 Receptor Bradykinin Angiotensin I (Inactive) Angiotensin II Vasodilation Na+ Excretion Bradykinin(1-7) (Inactive)

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

  17. 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 O2 consumption) • Diabetic Nephropathy • Dilates afferent and efferent renal arterioles • ↓Glomerular capillary pressure • ↓Growth of mesangial cells/matrix due to Ang II?

  18. 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) • ~0.1 - 0.5% of patients • Not dose-related; occurs within 1st week • Severe swelling of mouth, tongue, lips, airway • may be life-threatening

  19. 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

  20. 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

  21. 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

  22. Novel and Unexpected Functions of ACE and ACE inhibitors • ACE inhibitors induce protein crosstalk between ACE and bradykinin B2 receptor, enhancing signaling. • ACE inhibitors are direct agonists of the B1 kinin GPCR and induce endothelial nitric oxide production. • ACE inhibitor binding to ACE itself activates the MAP kinase JNK and stimulates gene transcription. See: Erdös EG, Tan F, and Skidgel RA. Angiotensin I-converting enzyme inhibitors are allosteric enhancers of kinin B1 and B2 receptor function. Hypertension 55: 214-220, 2010

  23. Other antihypertensive drugs that interfere with the Renin-Angiotensin System Angiotensinogen Kininogen Kallikrein Renin B2 Receptor Bradykinin Angiotensin I (Inactive) ACE Angiotensin II Vasodilation Na+ Excretion Angiotensin Receptor Antagonists (the “sartans”, e.g. Losartan) Bradykinin(1-7) (Inactive) AT1 Receptor Vasoconstriction Aldosterone release Na+ Retention Blood Pressure

  24. Other antihypertensive drugs that interfere with the Renin-Angiotensin System Angiotensinogen Kininogen Renin Inhibitor Aliskiren Kallikrein Renin B2 Receptor Bradykinin Angiotensin I (Inactive) ACE Angiotensin II Vasodilation Na+ Excretion Bradykinin(1-7) (Inactive) AT1 Receptor Vasoconstriction Aldosterone release Na+ Retention Blood Pressure

More Related