ACE Inhibitors
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Transcript of ACE Inhibitors
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.
Peptide Hormone Processing and Drug Development Strategies
Prohormone
Peptidase 1
Endoprotease
Active Peptide
Processing Enzyme
Receptor 1Receptor 2
Peptidase 2
Block Activity
Enhance Activity
Enhance Activity
Block Activity
ACE
C-domain
N-domain
ACE
ACE DISTRIBUTION
Widespread, concentrated on:• Endothelial surface of the vasculature
• Epithelial Brush borders
• Renal proximal tubules
• Small intestine
• Placenta
• Choroid plexus
ACE can cleave a variety of peptides
Structures of Clinically Used ACE Inhibitors
GlomerulusJuxtaglomerular Apparatus Regulation of Renin Release:
Renal Baroreceptor - senses pressure in wall of afferent arteriole; decrease stimulates renin secretionMacula Densa – senses chronic change in distal tubule salt delivery; decrease induces renin release.Sympathetic Nerves – JG cells are directly innervated by sympathetic nerves; stimulation increases renin secretionAngiotensin II- stimulates AT1 receptors on JG cells to decrease renin release
Angiotensinogen
Renin
Angiotensin I (Inactive)
Blood Pressure
Kininogen
Kallikrein
Bradykinin Kinin B2 Receptor
VasodilationNa+ 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
Proliferation of Sm. muscle/myocytes
Liver
ChymaseCathepsin G
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
Proliferation of Sm. muscle/myocytes
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
Angioedema
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
ACE
Angiotensinogen
Renin
Angiotensin I (Inactive)
Bradykinin B2 Receptor
AT1 Receptor
Angiotensin II
Bradykinin(1-7) (Inactive)
Blood Pressure
ARBs
Angiotensin (AT1R) Receptor Blockers (“ARBs” or “sartans”)
AT2 Receptor
AT1 Receptor
VasoconstrictionAldosterone release
Na+ RetentionPro-inflammatory Oxidative stress
Proliferation of Sm. muscle/myocytes
VasodilationNa+ Excretion
Anti-inflammatoryAnti-proliferative
ChymaseCathepsin G
Clinical Use of Angiotensin Receptor Blockers
Effects are Similar to those of ACE inhibitors
FDA Approved for: Hypertension
All ARBs Congestive Heart Failure
Valsartan approved (second line therapy if ACE inhibitors not tolerated)
Diabetic Nephropathy Irebesartan and Losartan (some believe superior to
ACE inhibitors)
Side Effects/Contraindications
Better tolerated than ACE inhibitors Much reduced risk of cough >2-fold lower risk of Angioedema
Other side effects, including fetopathic potential, the same as for ACE inhibitors
Renin Inhibitor
ACE
KininogenAngiotensinogen
Renin Kallikrein
Angiotensin I (Inactive)
Bradykinin B2 Receptor
AT1 Receptor
Angiotensin IIBradykinin(1-7) (Inactive)
Blood Pressure
ReninInhibitorAliskiren
VasodilationNa+ Excretion AT1
Receptor
VasoconstrictionAldosterone release
Na+ RetentionPro-inflammatory Oxidative stress
Proliferation of Sm. muscle/myocytes
ChymaseCathepsin G
Clinical Use of Aliskiren (Renin Inhibitor)
FDA Approved for Hypertension Currently being tested for use in Congestive Heart
Failure and Diabetic Nephropathy
Side Effects/Contraindications Generally well tolerated Teratogenic Low risk of cough and angioedema Most common side effects (<5%):
Gastrointestinal disturbance Headache/dizziness Hyperkalemia Rash (rare)