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)