ACE Inhibitors Hando.. - University of Illinois at Chicago

Download Report

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