Vasopeptidase Inhibition: Vasopeptidase Inhibition: A New Direction in A New Direction in

Cardiovascular Treatment Cardiovascular Treatment

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By: Dr. HARMANJIT SINGH MD STUDENT , GMC , PATIALA

INTRODUCTIONINTRODUCTION

• Essential hypertension remains one of the

most modifiable risk factors for

cardiovascular disease.

• Hypertension increases the risk of

cardiovascular disease in millions of

people worldwide.

• The estimate is that at least 43 million

people in the US have hypertension or are

taking antihypertensive medications.

• The Sixth National Joint Committee on the Prevention,

Detection, Evaluation and Treatment of Hypertension

(JNC-VI) has also addressed an another major issue

concerning aggressiveness of treatment.

• Until recently, there were no clear guideline on when to

initiate drug therapy in patients according to their blood

pressure and risk group stratification.

Risk stratification in patients with hypertensionRisk stratification in patients with hypertension

Risk Group A Risk Group B Risk Group C • No risk factor • No target – organ

disease/ clinical cardiovascular disease

• At least one risk factor, not including diabetes

• No target – organ disease/ clinical cardiovascular disease

• Target – organ disease/ cardiovascular disease and /or diabetes

• With or without other risk factors

Treatment strategies by risk stratification and risk Treatment strategies by risk stratification and risk group categories in patients with hypertension group categories in patients with hypertension

BP stages (mm Hg)

Treatment Strategy

Risk Group A Risk Group B Risk Group C

High-Normal (130-139 / 85-89)

Lifestyle modification

Lifestyle modification

Drug therapy, Lifestyle modification

Stage 1 (140-159 / 90-99)

Lifestyle modification upto 12 months

Lifestyle modification upto 6 months (patients with multiple factors should receive drug therapy + lifestyle modification)

Drug therapy, lifestyle modification

Stage 2 & 3 (> 160 / > 100)

Drug therapy, lifestyle modification

Drug therapy + lifestyle modification

Drug therapy + lifestyle modification

• This article focuses on a class of drugs, the

Vasopeptides Inhibitors (VPIs), which are designed

to address some of the above issues.

• These are new class of drugs that address both

hypertension and endothelial dysfunction.

• The VPIs work by affecting both the Renin Angiotensin

– Aldosterone System (RAAS) and the Natriuretic

Peptide System (NPS) simultaneously. We will discuss

both pathways, the new drug class itself, and some of

the clinical applications of this drug class.

Renin-Angiotensin System Renin-Angiotensin System • The role of the RAAS in cardiovascular disease has

already been established. It is an enzymatic cascade that results in the generation of the potent octapeptide hormone Angiotensin II.

• Angiotensin II is a potent vasoconstrictor as well as a stimulator of sodium and water retention via activation of aldosterone release.

• That is why ACE inhibitors are used for both hypertension and CHF.

Figure 1 showing role of RAS system in cardiovascular disease

• The initial demonstration of the survival benefit of the ACE inhibitor captoprill was seen in the CONSENSUS trial (Cooperative North Scandinavian Enalapril Survival Study) in 1987 among patients with New York Heart Association class IV CHF.

• This lead to numerous trials of ACE inhibitors in patients with class II and III heart failure.

• These studies such as SAVE (survival in ventricular enlargement), SOLVD (Studies of left ventricular dysfunction) and AIRE (Acute infarction Remipril Efficacy) have all demonstrated a survival benefit for patients with diminished left ventricular function.

• Angiotensin II can stimulate the secretion of plasminogen activator inhibitor-I (PAI-I) from the vascular endothelium.

• This substance is the major inhibitor of issue plasminogen activator.

• An increase in PAI-I levels would thus favour vascular thrombosis and result in potential increase in myocardial infarctions.

• So increased PAI-I is the risk factor for recurrent MI and ACE inhibition would decrease PAI-I levels and reduce the rate of recurrent infarction (20-25% reduction in the incidence of recurrent MIs).

• Until recently, the data suggesting that ACE inhibition

prevents vascular events have not been widely

accepted .

• The HOPE (Heart Outcomes Prevention Evaluation)

study was different in which 9297 high risk patients

with normal LV functions were randomly assigned to

receive placebo or ramipril 10 mg/ day.

• Treatment with ramipril significantly reduced the

incidence of overall cardiovascular deaths, myocardial

infarction and stroke.

• These facts were even more dramatic in patients with diabetes in whom ramipril also prevented the development of Overt nephropathy.

• As more information, on the importance of RAAS blockade becomes available, the need for newer and better drugs to interrupt this system becomes evident.

• Thus the emergence of this new class of drugs, the VPIs, marks and important step in antihypertensive drug development.

Hope Cntd……

Natriuretic Peptide System • De Bold et al (1981) discovered the first natriuretic

peptides by observing that when atrial tissue extracts

were infused into rats, natriuresis occurs.

• It was found that this peptide has natriuretic, diuretic

and vasorelaxant activity.

• Subsequently, three natriuretic peptides have been

isolated ANP i.e. atrial natriuretic peptide, BNP i.e. Brain

natriuretic peptide and CNP i.e. C-type natriuretic

peptide.

• These peptides were found to exert physiological effects at multiple sites resulting in the natriuresis, diuresis and vasodilatation, along with decreased aldosterone release, decrease cell growth, inhibition of the sympathetic nervous system and inhibition of RAAS.

• ANP produced by cardic atria, is stimulated by several substances such as endothelin, vasopressin and catecholamines, along with increased atrial wall tension.

• It results in natriuresis and diuresis in order to lower plasma volume and thus decreasing the atrial wall tension.

Natriuretic Pep Ctnd……

• BNP originally was found in porcine brains and human

brains, but considerably more is present in cardiac

ventricles.

• BNP have similar function as ANP and is also stimulated

by atrial distension.

• CNP predominates in the vascular wall.

• It potentiates vasodilatation and cell growth inhibition.

• It is found in the kidney, heart and lung in addition to the

vascular endothelium and respond to shear stress

• There is also a forth natriuretic peptide known as dendroaspis natriuretic peptide (DNP), isolated from the venom of the green Mamba snake but little is known about it.

• Neutral endopeptidase (NEP) is zinc containing enzyme

that catalyzes the breakdown of ANP, BNP and CNP to

inactive peptides.

• It also catalyses other peptide hormones like bradykinin

(a potent vasodilator and natriuretic factor), urodilatin (a

renal form of ANP) and adrenomedullin (a renal

vasodilating and natriuretic/ diuretic peptide).

• NEP is found in the brush border of the renal tubules,

lungs, intestine, adrenals, brain, heart and peripheral

vasculature.

Figure 2 showing the benefits of inhibiting NEP

• NEP inhibitors have been evaluated as antihypertensive agents but were found to be ineffective in humans.

• Candoxatril, a NEP inhibitor showed no effect on blood pressure when given twice daily for one month.

• One reason why does not work well as an antihypertensive agent when used alone may be related to Angiotension II levels.

• When given alone, NEP inhibitors raise angiotensin II levels, thus negating the possible positive effect that increasing ANP, BNP and CNP levels would have on blood pressure.

• When an NEP inhibitor is given in combination with an

ACE inhibitor blood pressure decreases markedly.

• In a spontaneously hypertensive rat model, it was

observed that there was marked decrease in blood

pressure. In hypertensive patients treated with

combination of NEP inhibitor and ACE inhibitor there

was marked decrease in B.P compared to NEP

inhibitor alone or ACE inhibitor alone.

• The additive effects of combined NEP and ACE

inhibition are related to inhibition of angiotensin II and

the potentiation of protective hormones such as

natriuretic peptides and bradykinin.

• On a molecular level, ACE inhibitors and NEP

inhibitors are similar in structure.

• As a result, researchers tried to develop a single drug

that would have both inhibitory actions.

• The VASOPEPTIDASE INHIBITORS became this

class.

VASOPEPTIDASE INHIBITORS • Both RAAS and NEP systems are important regulators

of blood pressure and vascular tones.

• Inhibition of the RAAS has significant benefits for treating patients with CHF and those at high risk for cardiovascular disease.

• The natriuretic peptides cause vasodilatation, natriuresis and diuresis.

• Because both ACE and NEP are zinc metallo proteases, development of drugs that can simultaneously inhibits both enzyme would have great potential.

• Several pharmaceutical groups have developed agents that inhibit both enzymes and have called this class of compounds “Vasopeptidase inhibitors (VPIs)”.

• One of these compounds is BMS-186716 (Omapatrilat), was selected for clinical development.

• Because it has near equal inhibitory potency against each enzyme the drug may be very useful for treating both hypertension and CHF.

• Figure 3 demonstrates the combined pathway involved.

Figure 3 showing combined pathways involved in vasopeptidase inhibition

VPIs IN HYPERTENSION

• In initial animal studies, omapatrilat reduced blood pressure in both sodium loaded and sodium depleted spontaneously hypertensive rats as well as in deoxycorticosterone acetate salts hypertensive rats.

• These findings indicate that the drug is an effective agent regardless of plasma renin levels.

• In more recent studies, omapatrilat was compared to captopril in hypertensive rats.

• The drugs had equal antihypertensive efficacy but omapatrilat had a greater efficacy on improving endothelium-dependent relaxation.

• In clinical trials, omapatrilat has decreased BP in

normal volunteers while preserving renal functions.

• Several randomized studies reported that the

omapatrilat caused statistically significant, dose

dependent decreases in both SBP and DBP.

• The drops in SBP averaged 15-25 mmHg and the

decreases in DBP were between 9-16 mmHg.

• Further, it was found that both urinary flow rate and

sodium excretions were increased along with drop in

BP in healthy volunteers (potent diuretic action).

• Both omapatrilat and the sampatrilat resulted in a

sustained antihypertensive effects in black hypertensive

patients.

• Sampatrilat was compared with lisinopril in these

studies. Both were equally safe but samapatrilat had a

greater antihypertensive effect than lisinopril.

• Because black persons are somewhat resistant to the

effects of ACE inhibitor, it is hypothesized that the

diuretic and natriuretic effect of sampatrilat accounted

for the greater effect.

• It is clear from these discussions that VPIs appear to

be extremely effective and safe anti-hypertensive

agents across a wide spectrum of patients.

• Their diuretic and natriuretic effects may make them

more effective single agents than ACE inhibitors or

angiotensin receptor blockers, while still affording

vascular protective effect seen with ace inhibitors.

• Only more research will answer this question.

VPIs IN CHF • Because of their dual action of ACE inhibition and

natriuresis and diuresis VPIs are natural agents to replace

ACE inhibitors in CHF.

• In animal models of tachycardia induced heart failure,

omapatrilat reduced both ventricular volume and wall stress

and also reduced left ventricular end diastolic pressures.

• The effect on left ventricular volume and stress was greater

than that seen with a combination of ACE inhibitor and

diuretic.

• This effect of VPIs has also been reported in two

rodent models.

• In cardiomyopathic hamsters, omapatrilat decreased

left ventricular end-diastolic pressure and was

associated with 40% increase in cardiac output and

47% decrease in PVR.

• In this model, neither ACE or NEP inhibitors alone had

a similar effect.

• Human studies have yielded similarly promising

results.

• Initial safety and efficacy studies (Ikram et al, 1999) have shown a sustained hemodynamic effect of omapatrilat in 369 patients with class II - IV heart failure.

• A slight increase in ejection fraction and a dose dependent decrease in mortality also occurred but the study lasted for only 12 weeks.

• Longer terms studies have yielded similar results.

• In another trial, by Kostis et al (2000) involving 1242 patients with class II – IV heart failure comparing omapatrilat with lisinopril for 24 weeks omapatrilat resulted in superior reduction in the primary end points; death or hospital admission for worsening heart failure compared with lisinopril.

• This possible superior effect of VPIs may well be due

to their renal effects.

• A series of studies have demonstrated a greater

natriuretic response with omapatrilat compared with

ACE inhibition.

• Also, there was a greater increase in GFR.

• So, they can be the potential drugs in the treatment of

CHF.

Other TrialsOther Trials• In the IMPRESS (Inhibition of

Metalloproteinase in a Randomized Exercise and Symptoms Study in Heart Failure) trial, 573 patients with CHF (63% NYHA class II and 37% NYHA class III/IV) were randomized to either omapatrilat (40 mg/d) or lisinopril (20 mg/d). 

• After 12 weeks, exercise tolerance increased similarly in both groups.

• Omapatrilat, however, lead to a better clinical status and lower incidence of the combined mortality/morbidity end points (ie, hospitalization and discontinuation of study medication for worsening heart failure) compared with lisinopril.

• Both drugs were well tolerated, but serious adverse events and marked elevations of creatinine were less frequent with omapatrilat

• The OCTAVE (Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril) study compared omapatrilat and enalapril in 25 000 patients with systolic hypertension and found 2.17% of patients onomapatrilat developed angioedema compared to 0.68% on enalapril.

• Rates were higher in African–American patients and smokers. Notably, some angioedema events were severe requiring intubation.

• It is not surprising that a higher incidence of angioedema is becoming apparent on the combined inhibitor when compared with pure ACE inhibition .

• In OVERTURE( Omapatrilat Versus Enalapril Randomized Trial)

• trial, 24 out of 2886 patients  incurred this complication whereas the rate with enalapril was 14 out of 2884 .

Adverse effects of VPIsAdverse effects of VPIs• Because of overlapping pharmacologic actions, some

adverse effects commonly seen with ACE inhibitors are also seen with omapatrilat.

• • Common adverse effects include cough, hypotension,

dizziness, increase in serum creatinine or blood urea nitrogen levels, and hyperkalemia.

• Large clinical trials report similar frequencies of cough and hyperkalemia as that seen with ACEIs

• Angioedema, a rare but serious adverse effect seen has been with omapatrilat which is believed to be a result of bradykinin accumulation.

• VPIs have the most potent inhibitory effect on bradykinin metabolism when compared with either an ACE inhibitor or NEP inhibitor alone. Angioedema was so severe that in some pts , intubation was required.

• Prevalence of angioedema associated with omapatrilat appears to be higher than that generally seen with ACE inhibitors. Because of this concern, the manufacturer withdrew omapatrilat's new drug application from the U.S. Food and Drug Administration .

• European Medicines Evaluation Agency and has initiated large-scale clinical trials to address this issue.

ConclusionConclusion• It is clear from the preceding discussions that the VPIs

are important new class of agents that have great potential in the treatment of both hypertension and CHF.

• The combined inhibition of ACE and NEP offers the advantages of the hemodynamic and vascular protective effects of ACE inhibition as well as the renal effects of NEP inhibition.

• With the development of more of these agents and as more extensive clinical trials are conducted, the benefit of the VPIs over other drugs should become apparent.

• Although they seems to be potential drug candidates

for the treatment of hypertension and CHF but

because of some serious adverse effects like

angioedema more of clinical safety data is required

before their approval for routine clinical use.

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