randal a. skidgel ace inhibitors from: skidgel and erdös, aha hypertension primer, 2008
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Randal A. SkidgelRandal A. Skidgel ACE Inhibitors
From: Skidgel and Erdös, 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 Erdös EG, Hypertension Primer, 4th Edition, Chap. A15, 2008.
Some Biologically Active PeptidesACTHACTH
AdrenomedullinAdrenomedullin
ß-Amyloid(1-40)ß-Amyloid(1-40)
Anaphylatoxins Anaphylatoxins
Angiotensin II Angiotensin II
Angiotensin(1-7) Angiotensin(1-7)
Atrial Natriuretic Peptide Atrial Natriuretic Peptide
BAM-12P, 18P & 22PBAM-12P, 18P & 22P
BombesinBombesin
Bradykinin Bradykinin
Brain Natriuretic PeptidesBrain Natriuretic Peptides
BuccalinBuccalin
Bursin Bursin
C-Type Natriuretic Peptide C-Type Natriuretic Peptide
Caerulein Caerulein
Calcitonin Calcitonin
Calcitonin Gene RelatedPeptideCalcitonin Gene RelatedPeptide
CardiodilatinCardiodilatin
CarnosineCarnosine
CASH (Cortical Androgen- Stimulating CASH (Cortical Androgen- Stimulating Hormone)Hormone)
CasomorphinsCasomorphins
CerebellinCerebellin
Cholecystokinin Cholecystokinin
ChromostatinChromostatin
CLIPCLIP
Contraceptive TetrapeptideContraceptive Tetrapeptide
Corticotropin Inhibiting PeptideCorticotropin Inhibiting Peptide
CorticostatinCorticostatin
Corticotropin ReleasingFactor Corticotropin ReleasingFactor
CytokinesCytokines
Delta Sleep-Inducing PeptideDelta Sleep-Inducing Peptide
Dermorphin Dermorphin
Dermaseptin Dermaseptin
Diabetes-Associated PeptideDiabetes-Associated Peptide
Diazepam Binding Inhibitor Diazepam Binding Inhibitor
Dynorphins Dynorphins
ß Endorphin ß Endorphin
Endothelins Endothelins
Met‑Enkephalin Met‑Enkephalin
Leu‑Enkephalin Leu‑Enkephalin
Epidermal Mitosis Inhibiting Peptide Epidermal Mitosis Inhibiting Peptide
ErythropoietinErythropoietin
Follicle Stimulating Hormone Follicle Stimulating Hormone
GalaninGalanin
Gastric Inhibitory Polypeptide Gastric Inhibitory Polypeptide
Gastrin Gastrin
Gastrin-Releasing PeptideGastrin-Releasing Peptide
α-Gliadorphinα-Gliadorphin
Granuliberin-RGranuliberin-R
Glucagon Glucagon
Glucagon-Like PeptideGlucagon-Like Peptide
Growth Factors Growth Factors
Growth HormoneGrowth Hormone
Growth Hormone‑ ReleasingHormone Growth Hormone‑ ReleasingHormone
GuanylinGuanylin
Inhibin Inhibin
Insulin Insulin
InterleukinsInterleukins
Kallidin Kallidin
KyotorphinKyotorphin
α & ß-Lactorphinα & ß-Lactorphin
Leucokinins Leucokinins
LipotropinLipotropin
Luteinizing Hormone (LH)Luteinizing Hormone (LH)
LH‑Releasing HormoneLH‑Releasing Hormone
MagaininsMagainins
MastoparanMastoparan
Melanin-ConcentratingMelanin-Concentrating
HormoneHormone
α‑Melanocyte Stimulatingα‑Melanocyte Stimulating
Hormone Hormone
MelanostatinMelanostatin
Morphine ModulatingMorphine Modulating
NeuropeptideNeuropeptide
MotilinMotilin
α‑Neoendorphinα‑Neoendorphin
ß‑Neoendorphinß‑Neoendorphin
Neurokinin ANeurokinin A
Neurokinin BNeurokinin B
Neuromedin NNeuromedin N
Neuropeptide YNeuropeptide Y
Neuropeptide PNeuropeptide P
ß-Neuroprotectinß-Neuroprotectin
NeurotensinNeurotensin
Neutrophil DefensinsNeutrophil Defensins
OrexinsOrexins
OxytocinOxytocin
PACAP (Pituitary Adenylate Cyclase Activating PACAP (Pituitary Adenylate Cyclase Activating Peptide)Peptide)
PancreastatinPancreastatin
Pancreatic PolypeptidePancreatic Polypeptide
Parathyroid HormoneParathyroid Hormone
Peptide Histidine IsoleucinePeptide Histidine Isoleucine
Peptide YYPeptide YY
ProlactinProlactin
ProctolinProctolin
RiginRigin
SecretinSecretin
SomatostatinSomatostatin
Substance PSubstance P
SysteminSystemin
ThymosinThymosin
ThyrotropinThyrotropin
Thyrotropin ReleasingThyrotropin Releasing
HormoneHormone
TuftsinTuftsin
UrocortinUrocortin
UroguanylinUroguanylin
Vasopressin (ADH)Vasopressin (ADH)
VIP (Vasoactive IntestinalVIP (Vasoactive Intestinal
Peptide)Peptide)
Prohormone
Peptidase 1
RK RR
Endoprotease
Active Peptide
Processing Enzyme
Receptor 1Receptor 2
Peptidase 2
Scheme of Peptide Hormone Processing & Metabolism
Strategies for Developing Therapeutic Agents
Peptidase 1
Active Peptide
Receptor 1Receptor 2
Peptidase 2
Administer the Peptide
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
Peptidase 1
Receptor 1Receptor 2
Peptidase 2
Block Degradation by Peptidases
Strategies for Developing Therapeutic Agents
Strategies for Developing Therapeutic Agents
Peptidase 1
Active Peptide
Receptor 1Receptor 2
Peptidase 2
Use a Receptor Antagonist
Prohormone
Peptidase 1
RK RR
Endoprotease
Active Peptide
Processing Enzyme
Receptor 1Receptor 2
Peptidase 2
Block Synthesis/Processing
Strategies for Developing Therapeutic Agents
ACE
ACE DISTRIBUTION
Widespread, concentrated on:
•Endothelial surface of the vasculature
•Epithelial Brush borders
•Renal proximal tubules
•Small intestine
•Placenta
•Choroid plexus
Structure of Human Angiotensin Converting Enzyme (ACE)
ACE
ACE
C-domain
N-domain
A given peptidase can cleave a variety of peptidesExample: Angiotensin Converting Enzyme (ACE)
Structures of Clinically Used ACE Inhibitors
Angiotensinogen
Renin
Angiotensin I (Inactive)
Blood Pressure
Kininogen
Kallikrein
Bradykinin Kinin B2 Receptor
Vasodilation
Na+ Excretion
Bradykinin(1-7) (Inactive)
ACE
ACE Inhibitors
Mechanism of Action of ACE Inhibitors
Angiotensin II
AT1 Receptor
VasoconstrictionAldosterone release
Na+ RetentionPro-inflammatory
Oxidative stress
Angiotensinogen
Renin
Angiotensin I (Inactive)
Angiotensin II
AT1 Receptor
Blood Pressure
Endopeptidases
Angiotensin 1-7 AT1-7/Mas Receptor
Angiotensin 1-5 (Inactive)
ACE
ACE Inhibitors
Mechanism of Action of ACE Inhibitors II
VasodilationNa+ ExcretionAnti-inflammatory Oxidative stress
VasoconstrictionAldosterone release
Na+ RetentionPro-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 Functions of ACE and ACE inhibitors
ACE inhibitors induce protein crosstalk between ACE and ACE inhibitors induce protein crosstalk between ACE and bradykinin B2 receptor, enhancing signaling.bradykinin B2 receptor, enhancing signaling.
ACE inhibitors are direct agonists of the B1 kinin GPCR and ACE inhibitors are direct agonists of the B1 kinin GPCR and induce endothelial nitric oxide production.induce endothelial nitric oxide production.
ACE inhibitor binding to ACE itself activates the MAP kinase ACE inhibitor binding to ACE itself activates the MAP kinase JNK and stimulates gene transcription.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
ACE
KininogenAngiotensinogen
Renin Kallikrein
Angiotensin I (Inactive)
Bradykinin B2 Receptor
AT1 Receptor
Angiotensin II
Vasoconstriction
Aldosterone release
Na+ Retention
Bradykinin(1-7) (Inactive)
Blood Pressure
AngiotensinReceptor
Antagonists(the “sartans”, e.g. Losartan)
Vasodilation
Na+ Excretion
Other antihypertensive drugs that interfere with the Renin-Angiotensin System
Other antihypertensive drugs that interfere with the Renin-Angiotensin System
ACE
KininogenAngiotensinogen
Renin Kallikrein
Angiotensin I (Inactive)
Bradykinin B2 Receptor
AT1 Receptor
Angiotensin II
Vasoconstriction
Aldosterone release
Na+ Retention
Bradykinin(1-7) (Inactive)
Blood Pressure
ReninInhibitorAliskiren
Vasodilation
Na+ Excretion
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