Randal A Skidgel ACE Inhibitors From Skidgel and Erd s AHA Hypertension Primer 2008 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 The Renin Angiotensin and Kallikrein Kinin Systems From Skidgel RA and Erd s EG Hypertension Primer 4th Edition Chap A15 2008 Some Biologically Active Peptides ACTH Adrenomedullin Amyloid 1 40 Anaphylatoxins Angiotensin II Angiotensin 1 7 Atrial Natriuretic Peptide BAM 12P 18P 22P Bombesin Bradykinin Brain Natriuretic Peptides Buccalin Bursin C Type Natriuretic Peptide Caerulein Calcitonin Calcitonin Gene RelatedPeptide Cardiodilatin Carnosine CASH Cortical Androgen Stimulating Hormone Casomorphins Cerebellin Cholecystokinin Chromostatin CLIP Contraceptive Tetrapeptide Corticotropin Inhibiting Peptide Corticostatin Corticotropin ReleasingFactor Cytokines Delta Sleep Inducing Peptide Dermorphin Dermaseptin Diabetes Associated Peptide Diazepam Binding Inhibitor Dynorphins Endorphin Endothelins Met Enkephalin Leu Enkephalin Epidermal Mitosis Inhibiting Peptide Erythropoietin Follicle Stimulating Hormone Galanin Gastric Inhibitory Polypeptide Gastrin Gastrin Releasing Peptide Gliadorphin Granuliberin R Glucagon Glucagon Like Peptide Growth Factors Growth Hormone Growth Hormone ReleasingHormone Guanylin Inhibin Insulin Interleukins Kallidin Kyotorphin Lactorphin Leucokinins Lipotropin Luteinizing Hormone LH LH Releasing Hormone Magainins Mastoparan Melanin Concentrating Hormone Melanocyte Stimulating Hormone Melanostatin Morphine Modulating Neuropeptide Motilin Neoendorphin Neoendorphin Neurokinin A Neurokinin B Neuromedin N Neuropeptide Y Neuropeptide P Neuroprotectin Neurotensin Neutrophil Defensins Orexins Oxytocin PACAP Pituitary Adenylate Peptide Pancreastatin Pancreatic Polypeptide Parathyroid Hormone Peptide Histidine Isoleucine Peptide YY Prolactin Proctolin Rigin Secretin Somatostatin Substance P Systemin Thymosin Thyrotropin Thyrotropin Releasing Hormone Tuftsin Urocortin Uroguanylin Vasopressin ADH VIP Vasoactive Intestinal Peptide Cyclase Activating Scheme of Peptide Hormone Processing Metabolism RK RR Prohormone Endoprotease Processing Enzyme Active Peptide Peptidase 1 Peptidase 2 r2 Recepto Receptor 1 Strategies for Developing Therapeutic Agents Administer the Peptide Active Peptide Peptidase 1 Peptidase 2 r2 Recepto Receptor 1 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 Strategies for Developing Therapeutic Agents Block Degradation by Peptidases Peptidase 1 Peptidase 2 r2 Recepto Receptor 1 Strategies for Developing Therapeutic Agents Use a Receptor Antagonist Active Peptide Peptidase 1 Peptidase 2 r2 Recepto Receptor 1 Strategies for Developing Therapeutic Agents RK RR Prohormone Endoprotease Block Synthesis Processing Processing Enzyme Active Peptide Peptidase 1 Peptidase 2 r2 Recepto Receptor 1 ACE DISTRIBUTION Widespread concentrated on Endothelial surface of the vasculature Epithelial Brush borders Renal proximal tubules Small intestine Placenta Choroid plexus ACE Structure of Human Angiotensin Converting Enzyme ACE N domain ACE C domain ACE A given peptidase can cleave a variety of peptides Example Angiotensin Converting Enzyme ACE Structures of Clinically Used ACE Inhibitors Mechanism of Action of ACE Inhibitors Angiotensinogen Kininogen ACE Inhibitors Renin Kallikrein Bradykinin Angiotensin I Inactive Kinin B2 Receptor ACE Angiotensin II AT1 Receptor Vasoconstriction Aldosterone release Na Retention Pro inflammatory Oxidative stress Bradykinin 1 7 Inactive Blood Pressure Vasodilation Na Excretion Mechanism of Action of ACE Inhibitors II Angiotensinogen Renin Endopeptidases Angiotensin 1 7 Angiotensin I AT1 7 Mas Receptor Inactive ACE Angiotensin II AT1 Receptor Vasoconstriction Aldosterone release Na Retention Pro inflammatory Oxidative stress Angiotensin 1 5 ACE Inhibitors Blood Pressure Inactive Vasodilation Na Excretion Anti inflammatory Oxidative stress 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 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 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 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 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 Novel and Unexpected
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