ACE Inhibitors Hando.. - University of Illinois at Chicago
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Transcript ACE Inhibitors Hando.. - University of Illinois at Chicago
Randal 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 Peptides
ACTH
Adrenomedullin
ß-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
ß Endorphin
Endothelins
Met-Enkephalin
Leu-Enkephalin
Epidermal Mitosis Inhibiting Peptide
Erythropoietin
Follicle Stimulating Hormone
Galanin
Gastric Inhibitory Polypeptide
Gastrin
Gastrin-Releasing Peptide
α-Gliadorphin
Granuliberin-R
Glucagon
Glucagon-Like Peptide
Growth Factors
Growth Hormone
Growth Hormone- ReleasingHormone
Guanylin
Inhibin
Insulin
Interleukins
Kallidin
Kyotorphin
α & ß-Lactorphin
Leucokinins
Lipotropin
Luteinizing Hormone (LH)
LH-Releasing Hormone
Magainins
Mastoparan
Melanin-Concentrating
Hormone
α-Melanocyte Stimulating
Hormone
Melanostatin
Morphine Modulating
Neuropeptide
Motilin
α-Neoendorphin
ß-Neoendorphin
Neurokinin A
Neurokinin B
Neuromedin N
Neuropeptide Y
Neuropeptide P
ß-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
Strategies for Developing Therapeutic Agents
Administer the Peptide
Active Peptide
Peptidase 1
Peptidase 2
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
Strategies for Developing Therapeutic Agents
Use a Receptor Antagonist
Active Peptide
Peptidase 1
Peptidase 2
Strategies for Developing Therapeutic Agents
RK
RR
Prohormone
Endoprotease
Block Synthesis/Processing
Processing Enzyme
Active Peptide
Peptidase 1
Peptidase 2
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
Bradykinin(1-7)
(Inactive)
AT1
Receptor
Vasoconstriction
Aldosterone release
Na+ Retention
Pro-inflammatory
Oxidative stress
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
Angiotensin 1-5
AT1
Receptor
Vasoconstriction
Aldosterone release
Na+ Retention
Pro-inflammatory
Oxidative stress
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 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
Other antihypertensive drugs that interfere with the Renin-Angiotensin System
Kininogen
Angiotensinogen
Kallikrein
Renin
Bradykinin
Angiotensin I
(Inactive)
B2
Receptor
ACE
Angiotensin II
AT1
Receptor
Angiotensin Bradykinin(1-7)
Receptor
(Inactive)
Antagonists
(the “sartans”,
e.g. Losartan)
Vasoconstriction
Aldosterone release
Na+ Retention
Blood
Pressure
Vasodilation
Na+ Excretion
Other antihypertensive drugs that interfere with the Renin-Angiotensin System
Kininogen
Angiotensinogen
Renin
Inhibitor
Aliskiren
Renin
Kallikrein
Bradykinin
Angiotensin I
(Inactive)
B2
Receptor
ACE
Angiotensin II
Bradykinin(1-7)
(Inactive)
AT1
Receptor
Vasoconstriction
Aldosterone release
Na+ Retention
Blood
Pressure
Vasodilation
Na+ Excretion