08/99 1

From Snake Venom to SAVE :The Benefits of Angiotensin-Converting

Enzyme Inhibitors and AT2 receptor blockade

by

John Hakim, M.D.

08/99 2

Outline on ACE talk

Renin-Angiotensin-Bradykinin System Brief History of ACE inhibitors and AT2 Blockers Mechanism of Action Clinical Indications

Hypertension CHF and LV dysfunction LV Dysfunction after MI Diabetic Nephropathy

Side Effects Conclusions

08/99 3

Renin-Angiotensin-Bradykinin System

Renin is secreted by kidneys by JG apparatus Angiotensinogen made by liver Renin cleaves of the decapeptide angiotensin 1 from

angiotensinogen ACE splits angiotensin 1 into angiotensin II during passage

through the lungs. Angiotensin II has blood pressure increasing effects ACE catalyzes breakdown of bradykinin to inactive peptides

08/99 4

Angiotensin Converting Enzyme: What is it?

Kinase 2 - a bivalent dipeptidyl carboxyl metalopeptidase

Two Forms: Endothelial ( on blood vessels and in brain) Soluble form in blood and body fluids

08/99 5

Yin and Yang of ACE

Bradykinin (via B2 receptor)

Promotes vasodilatation by stimulating production of arachodonic acid metabolites, NO, and endothelium derived hyperpolarizing factor

Promotes renal naturesis via direct tubular effects

Increases vascular permeability, augments mucus secretion

Angiotensin 2 Potent vasoconstrictor, acting

directly on vascular smooth muscle cells.

AT2 interacts with sympathetic nervous system both peripherally and centrally

Causes Sodium and fluid retention via aldosterone and ADH

Promotes cellular migration, proliferation and hypertrophy

Promotes growth of smooth muscle cells and hypertrophy of blood vessels and the heart.

08/99 6

History ACE inhibitors

1st ACE inhibitor was teprotide, an IV nonapepetide from venom of Bothrops jararaca isolated, elucidated, and synthesized 1971

Captopril was 1st oral ACE inhibitor (1978)

rapid onset of action with maximum activity in 15 to 30 minutes, but plasma T1/2 only 2 hours.

08/99 7

History ACE inhibitors

Newer ACE inhibitors Longer T1/2, more potent. Currently 9 oral ACE inhibitors approved by FDA-

Benazepril, Captopril, Enalapril, Fosinopril, Lisinopril, Moexipril, Ramapril, Quinapril, and Trandolapril

AT1 receptor antagonists (ARB)– Losartan, Valsartan, Irbesartan

08/99 8

ACE Pharmacology

Differences: Active Moieties

– sulfhydryl -Captopril– phosphinyl -Fosinopril– carboxyl -Enalapril,lisinopril, Benzapril, Quinapril, Ramapril,

Trandilopril, Moexipril

Potency & Plasma half life Distribution and affinity for tissue bound ACE Cardiac affinity

– quniapril=benazapril>lisinopril>fosinopril>captopril Excretion- all renal (fosinopril and trandolapril also metab by liver)

08/99 9

Angiotensin Receptors

Angiotensin receptors of AT1 subtype are the target of the new drugs Signal transduction by G Protien (Gq/11) which activates phospholipase

C to generate diacylglcerol and inositol triphosphate inositol triphosphate causes release of calcium from intracellular

stores Ca=2 and diacylglycerol activate protein kinases to phosphorolate

proteins and effect cell function gene is on Chromosome 3

AT2 receptor gene is on X chromosome

08/99 10

ACE Inhibitors: Clinical Indications

Hypertension Congestive Heart Failure LV dysfunction after Myocardial Infarction Atherosclerotic Vascular Disease Diabetic Nephropathy

08/99 11

Clinical Indications: Hypertension

ACE inhibitors decrease Systemic Vascular resistance but cause little change in heart rate

With chronic ACE inhibition, AT II and aldosterone levels tend to return to pretreatment levels (AJC 1982;49:1561-1563)

JNC VI has beta blockers and duretics as first line therapy for uncomplicated HTN

– ACE inhibitors are indicated for HTN with coexisting conditions such as CHF and DM Nephropathy

08/99 12

Clinical Indications: HypertensionRacial Differences

In VA Cooperative Study Group Trial, captopril reduced BP more in White patients with mild to moderate HTN than Black patients at 7 weeks.

These racial differences were abolished by the addition of HCTZ (BR J Clin Pharm 1982;14:97S-101S)

Racial Differences have not yet been noted with the AT2 Receptor Blockers

08/99 13

Congestive Heart Failure and LV Dysfunction

ACE Inhibitors have been shown to cause regression in LV Hypertrophy improve LV dysfunction decrease mortality in patients with CHF

Clinical trials CONSENSUS SOLVD-TREATMENT

V-HEFT II SOLVD-Prevention

08/99 14

High Cardiac affinity ACE

Quinipril - a high cardiac affinity ACE Has been shown to be superior to enalapril

in preventing LVH in animals

Circulation 1995;91;1 16-19 Relavance of Blockade of Cardiac and Circulatory ACE for theprevention of Volume Overload induced Cardiac Hypertrophy

08/99 15

ATB’s may be as effective as ACE in CHF

ELITE Study- “Evaluation of Losartan in the Elderly”

Reported equivalent effects of Losartan and Captopril in on the progression of CHF in elderly patients.

There was an unexpected reduction in the incidence of sudden death in the Losartan group.

Lancet 1997;349:747-752Randomized trial of Losartan vs Captopril

in patients over 65 with heart failure.

08/99 16

ACE Inhibitor Studies in LV Dysfunction post MI

SAVE NEJM 1992:327:669-667.

CONSENSUS II NEJM 1992;327:678-684

AIRE Lancet 1993;342:821-828

ISIS-4 Circulation 1993 Supplement I

GISSI 3 Lancet 1994;343:1115-1122

TRACE NEJM 1995;333:1670-1676

SMILE NEJM 1995;332:80-85

08/99 17

ACE Inhibitors Post MI

Subgroup analysis of SAVE (Uniformity of Captopril in SAVE Study) and TRACE (Trandolapril Cardiac Evaluation Study- ACE post MI) document beneficial effect of long term use of ACE inhibitors post MI

Beneficial effects in preventing LVH and Heart failure persist even when analysis were limited to diabetics.

08/99 18

ACE Inhibitors and Acute MIGISSI-3 analysis*

ACE inhibitor (lisinopril) reduced both six week (30%) and six month (20%) mortality (vs. placebo) in diabetics given drug within 24hours of admission.

Survival benefit was maintained for six months despite the fact that patients got drug for only six weeks.

Advantage was present in both IDDM and NIDDM. Patients with Cr>2.0, SBP<100mmHg, and Killip class 4

excluded.

*Circulation 1997;96:4239-4245. Zuanetti et al, Effect on Ace Inhibitor Lisinopril on mortality in diabetic patients with AMI.

08/99 19

ACE Inhibitors and Acute MI

Current guidelines in the treatment of AMI consider aspirin and fibrinolytics mandatory for all eligible patients.

Acute ACE inhibition appears to be particularly beneficial to Diabetics with MI. (Circulation 1997;96:4239-4245. Zuanetti et al, Effect on Ace Inhibitor Lisinopril on mortality in diabetic patients with AMI)

08/99 20

ACE Inhibitors and Ischemia

ACE inhibitors reduced recurrent MI by 25% in the SAVE Trial. (Circulation 1994;

90:1731-1738. Effects of Captopril on ischemia after myocardial infarction.)

ACE inhibition was associated with 37% fewer ischemic events in the CATS trial JACC

1997;30:400-405. Long term anti ischemic effects of angiotensin converting enzyme inhibitors in patients after myocardial infarction.

08/99 21

ACE Inhibitors and Ischemia

ACE inhibitors increases parasympathetic tone and helps restore the autonomic balance in CHF.

JACC 1993; 21:655-661. Sustained augmentation of

parasympathetic tone with angiotensin converting enzyme inhibition in patients with CHF.

ACE inhibitors may decrease central sympathetic outflow.

ACE inhibitors blunt sympathetic coronary vasoconstriction by decreasing angiotensin 2. Circulation

1997;96:148-153 Intracoronary Angiotensin 2 potentiates coronary artery sympathetic vasoconstriction in

Humans.

08/99 22

ACE Inhibitors and Remodeling

Remodeling of the LV post MI can be seen within 3 hours, with increased end-diastolic and end-systolic volumes.

Early Ramapril in Anterior Infarct was associated with substantial recovery of wall motion within 14 days post MI.**Circulation 1997; 95:2643-2651. Healing and Early Afterload Reducing Therapy (HEART) Trial Investigators.

08/99 23

Atherosclerotic Vascular Disease

Studies in LV dysfunction suggest ACE inhibitors decrease the frequency of ischemic events Several trials are underway to show ACE prevent ischemic events in

high risk patients without LV dysfunction

ACE inhibitors reverse endothelial dysfunction in hypertensive pts and pts with NIDDM

ACE Inhibitors improved endothelial function by enhancing bradykinin induced endothelial NO production

08/99 24

Diabetic Nephropathy

ACE inhibitors prevent progression of microalbuninuria to overt proteinuria.

A large, prospective placebo controlled study in IDDM has shown that captopril slows the progression of nephropathy to dialysis, transplant and death NEJM 1993;329:1456-1462

Effect is by selectively dilating efferent arterioles and decreasing glomerular filtration pressure.

08/99 25

ACE: SIDE EFFECTS

Class Effects– Hypotension, – Cough (10% Whites, up to 40% Asians)– Hyperkalemia, Renal Failure, Fetal anomalies, – Angioedema (2/1000 in whites higher in blacks)– Dysgeusia

Sulfhydryl-related effects (Captopril)– Neutropenia, Rash, Nephrotic -range proteinuria

08/99 26

AT2 receptor Blockers: Adverse Effects

Hypotension Impaired Renal Function Fetal/Neonatal Morbidity and Mortality

Please Note ATB are only indicated for Hypertension at Present

08/99 27

Conclusion

ACE Hypertension Congestive Heart Failure LV dysfunction after Myocardial Infarction Atherosclerotic Vascular Disease Diabetic Nephropathy

ATB Indicated for HTN Elderly (>65) with CHF benefit (less

sudden death and less CHF)

08/99 28

ATLAS Study

Compared low Dose to High Dose lisinopril vs. high Dose lisinopril

3000 pts, Class II, III, IV CHF All pts who could tolerate 12.5 mg lisinopril

randomized to 2.5-5mg vs 35mg lisinopril

08/99 29

ATLAS Results

High dose arm lower risk of death or hospitalization (12% reduction in all cause mortality and

hospitalization) Low Dose gives you 50% of the benefit of an

ACE inhibitor