President's Message

Contributed by M. Mohsen Ibrahim, MD
Sunday, 11 October 2015

President's Message

New Drugs for Hypertension

A Lesson in Molecular Biology

Two new pharmacologic agents are recently introduced for the control of hypertension; clevidipine and nepsilysin inhibitor/ ARB combination.  The first is for hypertensive emergency, while the second is for isolated systolic hypertension.

Clevidipine is a fourth generation calcium channel blocker. Clevidipine is a dihydropyridine L-type calcium channel blocker, highly selective for vascular, as opposed to myocardial, smooth muscle and, therefore, has little or no effect on myocardial contractility or cardiac conduction. It is a powerful arterial vasodilator with a rapid onset of action, short duration and great efficacy in lowering blood pressure. Its main role is in treatment of severe hypertension specially hypertensive heart failure. The initial phase half-life is approximately 1 minute and the terminal half-life is approximately 15 minutes.  Clevidipine is administered intravenously and should be titrated to achieve the desired blood pressure reduction. Blood pressure and heart rate should be monitored continually during infusion. An IV infusion at 1–2 mg/hour is recommended for initiation and should be titrated by doubling the dose every 90 seconds. In clinical trials, the safety profile of clevidipine was generally similar to sodium nitroprusside,nitroglycerin, or nicardipine in patients undergoing cardiac surgery. Clevidipine is contraindicated in patients with allergies to soybeans, soy products, eggs, or egg products and in patients with severe aortic stenosis.

The second agent is combined neprilysin inhibitor and ARB. Neprilysin is an enzyme (peptidase) responsible for the degradation of natriuretic peptides (NPs). NPs are a family of peptides which are released by cardiac and renal tissues as a response to increased cardiac wall stress and volume overload. These are four NPs, atrial (ANP), brain (BNP), renal (urodilatin URU) and endothelial cells (NCP). NPs stimulate cyclic guanosine monophosphate (cGMP) production which is a second messenger by binding to the guanyl cyclase (GC) receptor. cGMP modulates the activity of cGMP-dependent protein kinase (PKG), phosphodierterases and cation channels.

NPs form our main vasodilatory system counteracting the actions of the renin-angiotensin-aldosterone system (RAAS). In addition to vasodilation, NPs have diuretic and natriuretic effects and possess antihypertrophic antifibrotic and antiapoptatic actions.

The following is the NP action pathway:

Ligand (ANP) ? Receptor (Guanyl cyclase) ? second messenger (cGMP) ? Effector (PKG).

NPs are removed from the circulation through the kidneys and are inactivated by two mechanisms: clearance receptors (NP receptors) and degraded by peptidases including neprilysin.

NP system augmentation has now an established role when combined with ARBs in the treatment of heart failure. This was based on the results of the PARDIGM study. Recently this combination was used to treat high blood pressure. The valsartan/ sacubitril formerly known as LCZ 696 which won FAD approval for heart failure may also be a potent treatment for isolated systolic hypertension.

In the recent PARAMETER study, including 454 patients suggest that this drug may prove to be useful in treating hypertension. The reduction of both blood pressure and pulse pressure was remarkable. Pulse pressure is an independent risk factor for vascular events in the elderly. The new agent is possibly the first to successfully lower pulse pressure. PARAMETER assessed LCZ 696 (400 mg daily) after 12 weeks and 52 weeks in comparison with optimally dosed olmesartan (400mg). It recruited elderly patients who had both systolic hypertension and wide pulse pressure. The drug provided 24 hours blood pressure reduction. Central aortic pulse pressure decreased more in the LCZ 696 than in the control group.

The fact that neprilysia inhibitor- ARB combination is an effective blood pressure lowering medication is gaining recognition in the management of hypertension particularly in the difficult group of isolated systolic hypertension.

President of the EHS

M. Mohsen Ibrahim, MD

Prof. of Cardiology- Cairo University

Last Updated Monday, 12 October 2015