Angiotensinogen Angiotensin I Angiotensin II Angiotensin III Renin ACE Aminopeptidase Non-ACE ( eg. Chymase in heart ) Endopeptidase Angiotensin 1-7 Releases.

Angiotensinogen

Angiotensin I

Angiotensin II

Angiotensin III

Renin

ACE

Aminopeptidase

Non-ACE(eg. Chymase

in heart)

Endopeptidase

Angiotensin 1-7Releases ADH; ↑ PG;Natriuretic; ↓ RVR; ↓ BP (brain stem inj.)? Role in effects of ACEI

1 2 3 7 8 9 10

NH2-Asp-Arg-Val…Pro-Phe-COOH1 2 3 7 8 9 10

NH2-Asp-Arg-Val…Pro-Phe-COOH1 2 3 7 8

NH2-Arg-Val…Pro-Phe-COOH 2 3 7 8

NH2-Asp-Arg-Val…Pro-Phe-Hist-Leu…COOH

+

1. ↓ Renal PerfusionPressure2. ↓ Na at Macula Densa cells3. ↑ Sympathetic nerve activity (ß-1)

±PG

The Renin-Angiotensin System

Angiotensin II

Vasoconstriction

AldosteroneSecretion

Direct RenalSodium Retention

↑ Thirst

ADH Release

↑ Cardiac Contractility

Sympathetic Facilitation:CentralNerve terminal(ganglionic ?)

Cardiac & Vascular Hypertrophy

All known physiologic effects are mediated by the angiotensin II type 1 receptor

ANGIOTENSIN II - SUPPORT OF THE BLOOD PRESSURE

Angiotensin Converting Enzyme Inhibitors

Large number of drugs available differ mainly in the following:

1. Potency2. Route of elimination3. Duration of action4. Being prodrugs or active drugs Similar therapeutic indications, adverse

effects and contraindications

Adverse Effects

• Hypotension• Renal Insufficiency (if bilateral renal artery

stenosis)• Hyperkalemia – special group of patients (Na

restricted, on K-sparing diuretic, COX inhibitors)• Cough (20 %)• Angioedema• With captopril especially: neutropenia, nephrotic

syndrome, skin rash, taste disturbances (SH group- related).

Kinin-related (?)

Binds to active site

Binds to Zn ion

Binds more stronglyto Zn – more active

Enalapril Lisinopril

ACE Inhibitors and Left Ventricular Hypertrophy

ACE Inhibitors and Left Ventricular Hypertrophy

ACE Inhibitors after Myocardial Infarction

ACE Inhibitors in Heart Failure

Study of LV Dysfunction (SOLVD)

Survival and Ventricular Enlargement Trial (SAVE)Asymptomatic Patients with EF<40% ACE Inhibitors in Severe Heart Failure

Patients with Severe Heart FailureCooperative New Scandinavian Enalapril Survival Study (CONSENSUS)

Captopril

Placebo

Mor

tali

ty R

ate

Pro

bab

ilit

y of

Su

dd

en D

eath

Pro

bab

ilit

y of

Su

rviv

al

Captopril

Hydralazine

Enalapril

Placebo

ACE Inhibitors – Effect onProgression of Diabetic

Nephropathy

Enalapril

Enalapril

Metoprolol

Metoprolol

ACE Inhibitors – Effect onProgression of Non-Diabetic

Nephropathy

Therapeutic Uses

• Anti-hypertensive• Prevent or reverse LVH• Protect against sudden death and second

myocardial infarction after acute MI• Improve survival and hemodynamics in

patients with congestive heart failure• Protect against progression of diabetic and

non-diabetic nephropathy

Losartan

Valsartan

Candesartan

Angiotensin II Type 1 Receptor Blockers

Angiotensin Receptor Blockers e.g. Losartan

• Block only the AT-1 subtype• Comparable effects to ACE Inhibitors in almost

all situations.• Less decrease in GFR in volume depleted states• Less side effects especially cough, angioedema,

rash• Block all AII effects and not dependent on

particular pathway

Kinins(?)

P E LP LC

P: PlaceboE: EnalaprilL: LosartanC: Captopril

3 m

onth

mor

tali

ty (

%)

SOLVD US +Int’lExercise

ELITE

(n=2569) (n=722)(n=736)

Fig. 3: 3-month mortality in three different studies

ELITE STUDY GROUP (Evaluation of Losartan in the Elderly) – Losartan better than captopril in patients with heart failure (chance finding?)

Captopril

Losartan

ELITE STUDY GROUP Losartan Superior to Captopril (? Chance Finding)

Pro

bab

ility

of

Su

rviv

al

Follow-up (days)

ELITE II STUDY GROUP (3,152 patients for 1.5 y)No Difference between Captopril and Losartan

ProbabilityOf Survival %

Event-freeProbability %

Lancet. 2000;355:1582-7.

Hypertensive Patients with Nephropathy

ACE Inhibitor AII Receptor Blocker

Blocks formationof AII incompletely

Blocks Kininase II

↑ Kinins↓ AII effects & aldosterone

PROTECTION

Blocks AT-1R

AT-2R Free

More completeInhibition of AII effects

Preserve Anti-proliferativeeffect