Download Angiotensin-Converting Enzyme Inhibitors

From Snake Venom to SAVE :
The Benefits of Angiotensin-Converting
Enzyme Inhibitors
and AT2 receptor blockade
by
John Hakim, M.D.
08/99
1
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
2
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
3
Angiotensin Converting Enzyme: What is it?
Kinase 2 - a bivalent dipeptidyl carboxyl metalopeptidase
 Two Forms:



08/99
Endothelial ( on blood vessels and in brain)
Soluble form in blood and body fluids
4
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





08/99
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.
5
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
6
History ACE inhibitors

Newer ACE inhibitors
 Longer
T1/2, more potent.
 Currently 9 oral ACE inhibitors approved by FDABenazepril, Captopril, Enalapril, Fosinopril, Lisinopril,
Moexipril, Ramapril, Quinapril, and Trandolapril
 AT1 receptor
antagonists (ARB)
– Losartan, Valsartan, Irbesartan
08/99
7
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

08/99
Excretion- all renal (fosinopril and trandolapril also metab by liver)
8
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
9
ACE Inhibitors: Clinical Indications
Hypertension
 Congestive Heart Failure
 LV dysfunction after Myocardial Infarction
 Atherosclerotic Vascular Disease
 Diabetic Nephropathy

08/99
10
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
11
Clinical Indications: Hypertension
Racial 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
12
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


08/99
CONSENSUS
SOLVD-TREATMENT


V-HEFT II
SOLVD-Prevention
13
High Cardiac affinity ACE

Quinipril - a high cardiac affinity ACE

08/99
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 the
prevention of Volume Overload induced Cardiac Hypertrophy
14
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;349:747-752
Randomized trial of Losartan vs Captopril
in patients over 65 with heart failure.
08/99
15
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
16
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
17
ACE Inhibitors and Acute MI
GISSI-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
18
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
19
ACE Inhibitors and Ischemia

ACE inhibitors reduced recurrent MI by 25%
in the SAVE Trial.
(Circulation 1994; 90:17311738. 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
20
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
21
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
22
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
23
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
24
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
25
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
26
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
27
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
28
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
08/99
29