DOC PREVIEW
UIC PCOL 425 - ACE Inhibitors

This preview shows page 1-2-3-4-5 out of 14 pages.

Save
View full document
View full document
Premium Document
Do you want full access? Go Premium and unlock all 14 pages.
Access to all documents
Download any document
Ad free experience
View full document
Premium Document
Do you want full access? Go Premium and unlock all 14 pages.
Access to all documents
Download any document
Ad free experience
View full document
Premium Document
Do you want full access? Go Premium and unlock all 14 pages.
Access to all documents
Download any document
Ad free experience
View full document
Premium Document
Do you want full access? Go Premium and unlock all 14 pages.
Access to all documents
Download any document
Ad free experience
View full document
Premium Document
Do you want full access? Go Premium and unlock all 14 pages.
Access to all documents
Download any document
Ad free experience
Premium Document
Do you want full access? Go Premium and unlock all 14 pages.
Access to all documents
Download any document
Ad free experience

Unformatted text preview:

1 Randal A. SkidgelDept. of PharmacologyACE InhibitorsFrom: Skidgel and Erdös, Hypertension Primer, 2008 ACE = Angiotensin I Converting Enzyme 10 ACE inhibitors available in US: benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril. Lisinopril was the 4th most prescribed drug in the US in 2005 with 47,829,000 prescriptions written2 Some Biologically Active PeptidesACTHAdrenomedullinß-Amyloid(1-40)Anaphylatoxins Angiotensin II Angiotensin(1-7) Atrial Natriuretic Peptide BAM-12P, 18P & 22PBombesinBradykinin Brain Natriuretic PeptidesBuccalinBursin C-Type Natriuretic Peptide Caerulein Calcitonin Calcitonin Gene RelatedPeptideCardiodilatinCarnosineCASH (Cortical Androgen- Stimulating Hormone)CasomorphinsCerebellinCholecystokinin ChromostatinCLIPContraceptive TetrapeptideCorticotropin Inhibiting PeptideCorticostatinCorticotropin ReleasingFactor CytokinesDelta Sleep-Inducing PeptideDermorphin Dermaseptin Diabetes-Associated PeptideDiazepam Binding Inhibitor Dynorphins ß Endorphin Endothelins Met-Enkephalin Leu-Enkephalin Epidermal Mitosis Inhibiting Peptide ErythropoietinFollicle Stimulating Hormone GalaninGastric Inhibitory Polypeptide Gastrin Gastrin-Releasing Peptideα-GliadorphinGranuliberin-RGlucagon Glucagon-Like PeptideGrowth Factors Growth HormoneGrowth Hormone- ReleasingHormone GuanylinInhibin Insulin InterleukinsKallidin Kyotorphinα & ß-LactorphinLeucokinins LipotropinLuteinizing Hormone (LH)LH-Releasing HormoneMagaininsMastoparanMelanin-ConcentratingHormoneα-Melanocyte StimulatingHormone MelanostatinMorphine ModulatingNeuropeptideMotilinα-Neoendorphinß-NeoendorphinNeurokinin ANeurokinin BNeuromedin NNeuropeptide YNeuropeptide Pß-NeuroprotectinNeurotensinNeutrophil DefensinsOrexinsOxytocinPACAP (Pituitary Adenylate Cyclase Activating Peptide)PancreastatinPancreatic PolypeptideParathyroid HormonePeptide Histidine IsoleucinePeptide YYProlactinProctolinRiginSecretinSomatostatinSubstance PSysteminThymosinThyrotropinThyrotropin ReleasingHormoneTuftsinUrocortinUroguanylinVasopressin (ADH)VIP (Vasoactive IntestinalPeptide) Endogenously generated peptides are involved in the physiology and pathology of all major organ systems and play important roles in many processes. These include neurotransmission, immune function, cell proliferation, pain/analgesia, fluid balance in the kidney, endocrine functions, reproduction, contraction/relaxation of all types of smooth muscle, regulation of the cardiovascular system, satiety/obesity, etc.1. TO MIMIC THE ACTION OF A PEPTIDE:A. Administer the Peptide or non-peptide agonist of the receptor (See above for advantages/disadvantages).B. Stimulate Endogenous Synthesis of the Peptide – This approach is unlikely to be successful as most processing enzymes are already fully active and enhancing processing might affect processing of other peptides. Specifically upregulating transcription of the precursor will be difficult to achieve in vivo and may overwhelm the processing pathway, leading to releaseof incompletely processed and inactive peptides. C. Block the Degradation by Peptidase(s) - This is a good strategy because the level of the peptide can be specifically increased at its normal site(s) of action and peptidase inhibitors can be synthesized with good stability and bioavailability. Disadvantages include: 1) Blocking one peptidase may interfere with the metabolism of more than one peptide; 2) Inhibition ofmore than one peptidase may be needed to block the degradation of a peptide 3) Enhancing general levels of a peptide with multiple actions may produce side-effects. 2. TO BLOCK THE ACTION OF A PEPTIDE:A. Enhance Degradation by Activating Peptidases or Administer Enzyme. This is not a desirable approach for the following reasons: 1) Probably not possible to activate peptidases as most are present in their fully active form; 2) Activationorfollowing reasons: 1) Probably not possible to activate peptidases as most are present in their fully active form; 2) Activation or administration of a peptidase would likely enhance the degradation of many peptides. 3) Delivery of enzyme to the site of actionmay be difficult. 4) Generating and purifying large quantities of an enzyme is economically prohibitive.B. Use a Receptor Antagonist – This is an excellent approach because the specific actions of a peptide mediated by a single receptor type can be blocked, leading to the potential for few unwanted side effects. However, many peptide receptor antagonists are themselves peptides and suffer from the disadvantages listed above. Development of non-peptide antagonists may with good bioavailability and stability is possible, but is still not a straightforward process.C. Block the Synthesis/Processing of the Peptide – This is also an excellent approach and one exemplified by the development of Angiotensin Converting Enzyme (ACE) inhibitors. In this approach, all the actions of the peptide can be blocked and enzyme inhibitors can be synthesized with high affinity specificity and bioavailability However disadvantages includethe4and enzyme inhibitors can be synthesized with high affinity, specificity and bioavailability. However, disadvantages includethe following: 1) Cannot block a specific action of a peptide if it acts on more than one receptor. 2) Intermediate forms of a peptide that build up when processing is blocked may have their own biological activity. 3)Processing enzymes may process other peptide hormones. (ACE inhibitors do not suffer this disadvantage as the Renin-Angiotensin system specifically processes and generates only angiotensin and not other peptides).3 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 Expensive to synthesize (~$100,000/kg vs. pennies/kg)ACEACE DISTRIBUTION Widespread, concentrated on:•Endothelial surface of the vasculature•Epithelial Brush


View Full Document

UIC PCOL 425 - ACE Inhibitors

Documents in this Course
Exam 3

Exam 3

7 pages

Kozasa

Kozasa

14 pages

Load more
Download ACE Inhibitors
Our administrator received your request to download this document. We will send you the file to your email shortly.
Loading Unlocking...
Login

Join to view ACE Inhibitors and access 3M+ class-specific study document.

or
We will never post anything without your permission.
Don't have an account?
Sign Up

Join to view ACE Inhibitors 2 2 and access 3M+ class-specific study document.

or

By creating an account you agree to our Privacy Policy and Terms Of Use

Already a member?